Experimental Model Of Atrial Fibrillation Research Articles

Abstract 18630: Variance In Endocardial Voltage Between The Sinus Node And Other Bi-atrial Regions In Patients With Atrial Fibrillation

Background: The mechanisms for atrial fibrillation (AF) are unclear but correlate with substrates such as low voltage and CHADS2VASc risk factors, which is a target for AF ablation after the recent ERASE trial. Experimental models of AF show that fibrosis increases near the sinus node, which may explain the link between AF and sinus node dysfunction. However, such data are less clear in patients without global mapping of all regions simultaneously. Hypothesis: We hypothesize that there is a difference in regional endocardial voltages in AF patients mapping globally, specifically between the sinus node and other atrial regions. Methods: We studied N = 57 patients undergoing AF ablation with bi-atrial global endocardial voltage data (19 females, LVEF 58 ± 1.5%). Electrograms were collected using 64 pole basket catheters in the right (RA) and left (LA) atrium for 1 minute. We used custom software to analyze 3D electroanatomic maps (NavX, Abbott, IL) for voltages in 3 predefined regions in the RA near and remote from the sinus node, and in the LA (Fig 1). Results: Patients exhibited lower voltages in the lateral RA (0.43 ± 0.05 vs 0.66 ± 0.06 mV; p < 0.05), and the RA septum (0.46 ± 0.04 vs 0.66 ± 0.06 mV; p < 0.05) compared to the sinus node, respectively. Patients also exhibited lower voltages in the lateral RA compared to the LA roof (0.43 ± 0.05 vs 0.57 ± 0.05 mV; p < 0.05). The difference between the sinus node and the LA roof (0.66 ± 0.06 vs 0.57 ± 0.05; p > 0.05) and other regions failed to reach significance. No difference between combined right atrial voltage and left atrial voltage was found. Differences were maintained for successive time windows over 1 minute. Conclusion: We observed consistent regional variations in atrial voltage in AF patients, and higher voltage in the sinus node than other regions. Future studies should determine if this underlies the link between AF and sinus node dysfunction, and if this varies in comorbidities such as diabetes mellitus.

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses.

Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e., electropathology). Insights into AF-induced transcriptomic alterations may aid in a deeper understanding of electropathology. Specifically, RNA sequencing (RNA-seq) facilitates transcriptomic analyses and discovery of differences in gene expression profiles between patient groups. In the last decade, various RNA-seq studies have been conducted in atrial tissue samples of patients with AF versus controls in sinus rhythm. Identified differentially expressed molecular pathways so far include pathways related to mechanotransduction, ECM remodeling, ion channel signaling, and structural tissue organization through developmental and inflammatory signaling pathways. In this review, we provide an overview of the available human AF RNA-seq studies and highlight the molecular pathways identified. Additionally, a comparison is made between human RNA-seq findings with findings from experimental AF model systems and we discuss contrasting findings. Finally, we elaborate on new exciting RNA-seq approaches, including single-nucleotide variants, spatial transcriptomics and profiling of different populations of total RNA, small RNA and long non-coding RNA.

Increased Density of Endogenous Adenosine A2A Receptors in Atrial Fibrillation: From Cellular and Porcine Models to Human Patients.

Adenosine, an endogenous nucleoside, plays a critical role in maintaining homeostasis during stressful situations, such as energy deprivation or cellular damage. Therefore, extracellular adenosine is generated locally in tissues under conditions such as hypoxia, ischemia, or inflammation. In fact, plasma levels of adenosine in patients with atrial fibrillation (AF) are elevated, which also correlates with an increased density of adenosine A2A receptors (A2ARs) both in the right atrium and in peripheral blood mononuclear cells (PBMCs). The complexity of adenosine-mediated effects in health and disease requires simple and reproducible experimental models of AF. Here, we generate two AF models, namely the cardiomyocyte cell line HL-1 submitted to Anemonia toxin II (ATX-II) and a large animal model of AF, the right atrium tachypaced pig (A-TP). We evaluated the density of endogenous A2AR in those AF models. Treatment of HL-1 cells with ATX-II reduced cell viability, while the density of A2AR increased significantly, as previously observed in cardiomyocytes with AF. Next, we generated the animal model of AF based on tachypacing pigs. In particular, the density of the key calcium regulatory protein calsequestrin-2 was reduced in A-TP animals, which is consistent with the atrial remodelling shown in humans suffering from AF. Likewise, the density of A2AR in the atrium of the AF pig model increased significantly, as also shown in the biopsies of the right atrium of subjects with AF. Overall, our findings revealed that these two experimental models of AF mimicked the alterations in A2AR density observed in patients with AF, making them attractive models for studying the adenosinergic system in AF.

Shunt and pace: a novel experimental model of atrial fibrillation with a volume-loaded left atrium.

Atrial fibrillation (AF) is frequently seen in patients with a volume-loaded left atrium (LA) such as mitral valve regurgitation (MR). Previous animal models have incomplete relevance to human AF associated with MR. A novel experimental model with a combination of volume loading of LA by creating a shunt from the subclavian artery to pulmonary artery and electrical remodeling induced by continuous rapid LA pacing was designed and the electrophysiological effects were examined in 10 canines. Five weeks after the shunt surgery, the entire atrial epicardium was mapped during sustained AF with form-fitted electrode patches with 246 bipolar electrodes and a three-dimensional dynamic mapping system to characterize the induced AF. Three animals died of severe heart failure and pacing failure occurred in one. Remaining six animals were subjected to the analysis. The LA diameter increased progressively after the shunt surgery. Sustained AF was induced after 3 weeks of continuous rapid LA pacing in all animals. The activation maps revealed repetitive focal activations arising from the pulmonary veins, right or left atrial regions, and reentrant activations in the RA, which patterns of atrial activations are the same as those seen in human AF. The animal model with a combination of LA volume load and electrical remodeling was relevant to human AF associated with LA volume load. Studies using the present model may provide further knowledges of AF and may be useful in examining the effects of pharmacological and non-pharmacological therapies.

Inhibition of KCa3.1 Channels Suppresses Atrial Fibrillation via the Attenuation of Macrophage Pro-inflammatory Polarization in a Canine Model With Prolonged Rapid Atrial Pacing.

Aims: To investigate the role of KCa3. 1 inhibition in macrophage pro-inflammatory polarization and vulnerability to atrial fibrillation (AF) in a canine model with prolonged rapid atrial pacing.Materials and Methods: Twenty beagle dogs (weighing 8–10 kg) were randomly assigned to a sham group (n = 6), pacing group (n = 7) and pacing+TRAM-34 group (n = 7). An experimental model of AF was established by rapid pacing. TRAM-34 was administered to the Pacing+TRAM-34 group by slow intravenous injection (10 mg/kg), 3 times each day. After 7 days of pacing, the electrophysiology was measured in vivo. The levels of interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), CD68, c-Fos, p38, and NF-κB p65 in both atriums were measured by Western blotting, and the levels of inducible nitric oxide synthase (iNOS) and arginase1 (Arg-1) were measured by real-time PCR. Macrophage and KCa3.1 in macrophage in the atrium were quantized following double labeled immunofluorescent.Results: Greater inducibility of AF, an extended duration of AF and lower atrial effective refractory period (AERP) were observed in the pacing group compared with those in the sham group. Both CD68-labeled macrophage and the expression of KCa3.1 in macrophage were elevated in the pacing group and inhibited by TRAM-34, led to higher iNOS expression, lower Arg-1 expression, elevated levels of IL-1β, MCP-1, and TNF-α in the atria, which could be reversed by TRAM-34 treatment (all P < 0.01). KCa3.1 channels were possibly activated via the p38/AP-1/NF-κB signaling pathway.Conclusions: Inhibition of KCa3.1 suppresses vulnerability to AF by attenuating macrophage pro-inflammatory polarization and inflammatory cytokine secretion in a canine model with prolonged rapid atrial pacing.

Cardioprotective Role of Heat Shock Proteins in Atrial Fibrillation: From Mechanism of Action to Therapeutic and Diagnostic Target.

Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment.

Antiarrhythmic effect of ranolazine in combination with selective NCX-inhibition in an experimental model of atrial fibrillation

Abstract Background Previous studies showed an antiarrhythmic effect of ranolazine in different clinical and experimental studies. The aim of this study was to investigate the effects of a combination of ranolazine with different selective NCX-inhibitors in an established experimental model of atrial fibrillation. Methods and results 18 hearts of New Zealand white rabbits were retrogradely perfused. Left and right atrial catheters were used to record monophasic action potentials. Hearts were paced at three different cycle lengths (350ms, 250ms, 150ms). Thereby, cycle-length dependent atrial action potential durations (aAPD90), atrial effective refractory periods (aERP) and atrial post-repolarization refractoriness (aPRR=aERP-aAPD90) were obtained. Vulnerability to AF was tested by a standardized protocol employing several trains of burst pacing. After generating baseline data, the hearts were perfused with a combination of acetylcholine (ACh, 1μM) and isoproterenol (Iso, 1μM) to increase occurrence of AF. Afterwards, the hearts were assigned to two groups and additionally perfused with a combination of 10 μM ranolazine and 1 μM of the selective NCX-inhibitor ORM-10103 (group 1: Rano-ORM) or 10 μM ranolazine and 1 μM of another NCX-inhibitor, SEA0400 (group 2: Rano-SEA). Infusion of ACh/Iso led to a shortening of aAPD90 (group 1/2: −27.2ms/−24.5ms p&amp;lt;0.05), aERP (−29.2ms/−35.6ms p&amp;lt;0.05), aPRR (−12.2ms/−13.7ms p=ns) and the occurrence of AF-Episodes was significantly increased (group 1: baseline 6 episodes to 34 episodes under ACh/Iso p&amp;lt;0.05, group 2: baseline 7 episodes to 26 episodes under ACh/Iso p&amp;lt;0.05). Additional perfusion with ranolazine and ORM-10103 did not alter aAPD90 (−0,47ms) while effective refractory periods (+21.4ms, p&amp;lt;0.05) and aPRR (+43ms, p&amp;lt;0.05) were significantly prolonged and AF episodes were effectively reduced to 15 episodes (p&amp;lt;0.05). In group 2, Rano-SEA led to a slight decrease in aAPD90 (−9.5ms) while aERP (+13.3ms, p&amp;lt;0.05) and aPRR (+19.8ms, p&amp;lt;0.05) were prolonged. The occurrence of AF episodes was reduced to 15 episodes (p=0.1). Conclusion To our knowledge this is the first study investigating the effect of ranolazine combined with different selective NCX-inhibitors in an isolated whole-heart model of AF. Atrial repolarization was not significantly changed with either of the combinations. However, both combinations prolonged aERP and aPRR and thereby suppressed induction of AF. Combining novel cellular targets may therefore lead to new potentially interesting options for antiarrhythmic AF therapy that have to be tested in clinical studies. Funding Acknowledgement Type of funding source: None

Antiarrhythmic Effect of Ranolazine in Combination with Selective NCX-Inhibition in an Experimental Model of Atrial Fibrillation

The aim of this study was to investigate the effects of a combination of ranolazine with different selective inhibitors of the Na+/Ca2+-exchanger (NCX) in an established experimental model of atrial fibrillation (AF). Eighteen hearts of New Zealand white rabbits were retrogradely perfused. Atrial catheters were used to record monophasic action potentials (aPRR). Hearts were paced at three different cycle lengths. Thereby, atrial action potential durations (aAPD90), atrial effective refractory periods (aERP) and atrial post-repolarization refractoriness were obtained. Isoproterenol and acetylcholine were employed to increase the occurrence of AF. Thereafter, the hearts were assigned to two groups (n = 9 each group) and additionally perfused with a combination of 10 µM ranolazine and 1 µM of the selective NCX-inhibitor ORM-10103 (group A: Rano-ORM) or 10 µM ranolazine and 1 µM of another NCX-inhibitor, SEA0400 (group B: Rano-SEA). The infusion of Iso/ACh led to a shortening of aAPD90, aERP, aPRR and the occurrence of AF episodes was significantly increased. Additional perfusion with ranolazine and ORM-10103 (group A) significantly prolonged the refractory periods and aPRR and AF episodes were effectively reduced. In group B, Rano-SEA led to a slight decrease in aAPD90 while aERP and aPRR were prolonged. The occurrence of AF episodes was consecutively reduced. To our knowledge, this is the first study investigating the effect of ranolazine combined with different selective NCX-inhibitors in an isolated whole-heart model of AF. Both combinations prolonged aERP and aPRR and thereby suppressed the induction of AF.

Heat shock protein inducer reverses the contractile and structural remodeling of HL-1 cardiomyocytes in experimental model of Atrial Fibrillation

Background: Atrial Fibrillation (AF) is the most common tachyarrhythmia associated with electrical, structural remodeling and contractile dysfunction, which is rooted in an impaired protein quality control (PQC) system. PQC regulates the correct folding, trafficking and degradation of proteins in cells. Heat shock proteins (HSPs) play a critical role in facilitating the PQC. Our previous studies showed that the HSP inducers geranylgeranylaceton (GGA) and its derivatives prevent contractile dysfunction in tachypaced atrial cardiomyocyte and Drosophila model for AF. Here we tested whether the potent HSP inducer GGA59 also restores contractile dysfunction in tachypaced cardiomyocytes and explored the underlying mechanisms.

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca2+-Activated K+ Current in Patients with Chronic Atrial Fibrillation.

BackgroundIncreased small-conductance Ca2+-activated K+ current (SK), abnormal intracellular Ca2+ handling, and enhanced expression and activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been found in clinical and/or experimental models of atrial fibrillation (AF), but the cumulative effect of these phenomena and their mechanisms in AF are still unclear. This study aimed to test the hypothesis that CaMKII increases SK current in human chronic AF.Material/MethodsRight atrial appendage tissues from patients with either sinus rhythm (SR) or AF and neonatal rat atrial myocytes were used. Patch clamp, qRT-PCR, and Western blotting techniques were used to perform the study.ResultsCompared to SR, the apamin-sensitive SK current (IKAS) was significantly increased, but the mRNA and protein levels of SK1, SK2, and SK3 were significantly decreased. In AF, the steady-state Ca2+ response curve of IKAS was shifted leftward and the [Ca2+]i level was significantly increased. CaMKII inhibitors (KN-93 or autocamtide-2-related inhibitory peptide (AIP)) reduced the IKAS in both AF and SR. The inhibitory effect of KN-93 or AIP on IKAS was greater in AF than in SR. The expression levels of calmodulin, CaMKII, and autophosphorylated CaMKII at Thr287 (but not at Thr286) were significantly increased in AF. Furthermore, KN-93 inhibited the expression of (Thr287)p-CaMKII and SK2 in neonatal rat atrial myocytes.ConclusionsSK current is increased via the enhanced activation of CaMKII in patients with AF. This finding may explain the difference between SK current and channels expression in AF, and thus may provide a therapeutic target for AF.

CREM-transgene mice: An animal model of atrial fibrillation and thrombogenesis

BackgroundThe molecular pathomechanisms underlying atrial thrombogenesis are multifactorial and still require detailed investigations. Transgenic mice with cardiomyocyte-directed expression of the transcriptional repressor CREM-IbΔC-X (CREM-TG) represent an experimental model of atrial fibrillation (AF) that shows a gradual, age-dependent progression from atrial ectopy to persistent AF. Importantly, this model develops biatrial thrombi. The molecular characteristics related to the thrombogenesis in CREM-TG mice have not been studied, yet. MethodsThe inflammatory and prothrombotic state was evaluated at the transcriptional (qRT-PCR) and protein level in the left (LA) and right atria (RA) from CREM-TG mice at the age of 20weeks and compared to wild-type controls. Moreover, histological analyses of atrial thrombi were performed. ResultsThe endocardial dysfunction was mirrored by diminished levels of eNOS-mRNA in both atria (RA: 0.79±0.04, LA: 0.72±0.06; each P<0.05). Moreover, the PAI-1/t-PA mRNA ratio was significantly increased in both atria (RA: 3.6±0.6; P<0.01, LA: 4.0±1.0; P<0.05) indicating a high risk of thrombus formation. However, the inflammatory phenotype was more pronounced in the RA and was reflected by a significant increase in the mRNA levels encoding adhesion molecules ICAM-1 (2.1±0.2; P<0.01), VCAM-1 (2.3±0.5; P<0.05), and selectin P (3.6±0.5: P<0.05). ConclusionsCREM-TG mice represent a valuable model for studying atrial thrombogenesis and assessing therapeutic approaches preventing embolic events in the systemic and pulmonary circulation.

Modeling Atrial Fibrillation using Human Embryonic Stem Cell-Derived Atrial Tissue

Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.

Abstract 18323: Positive Frequency-Dependent Effects of Highly Selective Kv1.5 Blockers (XEN-D0103 &amp; MK-0448) in Right Atrial Trabeculae From Patients in Sinus Rhythm

Aim: Despite promising effects of Kv1.5 blockers in experimental models of atrial fibrillation, limited data is available for man. Therefore we investigated two selective Kv1.5 channel blockers, XEN-D0103 and MK-0448, on atrial myocardium from patients in sinus rhythm (SR). Method: Kv1.5 currents were measured with in CHO cells expressing hKv1.5. Sharp microelectrodes were used to record action potentials (AP) at various stimulation frequencies (37°C) in right atrial trabeculae from consenting patients in SR. Results: Kv1.5 was activated by voltage-clamp steps from -80 to 0mV (900ms)at 0.2Hz (room temp). XEN-D0103 and MK-0448 inhibited Kv1.5 with IC50 of 25nM and 32nM resp.. Both compounds display &gt;500-fold selectivity over hERG, Kv4.3, Nav1.5, Cav1.2, Kir2.1. The plateau phase of the atrial AP was elevated with XEN-D0103 and MK-0448 in a concentration-dependent manner. At 1Hz this effect was associated with shortening of APD90 and of effective refractory period (ERP) (see Table). At higher stimulation rates the APD90 and ERP shortening effects of XEN-D0103 and MK-0448 (3μM each) diminished and eventually converted to prolongation. With XEN-D0103, significant prolongation of APD90/ERP occurred at 3Hz and higher rates. In control, 10 out of 16 trabeculae followed stimulation at 5Hz, however, in the presence of XEN-D0103 10 out of 10, and with MK-0448 4 out of 6 preparations failed to capture stimulation. Conclusion: This is the first report of robust frequency dependence of selective Kv1.5 channel blockers in human atrial myocardium suggesting that these drugs are more effective at high than at low activation rates. Therefore, XEN-D0103 and MK-0448 should possess potential for suppressing episodes of rapid atrial excitation. Table: Frequency-dependent effects of the Kv1.5 blockers XEN-D0103 and MK-0448 in human right atrial trabeculae. Differences between pre-drug controls and values after 1 hour of drug superfusion (means ± SEM).

The Role of Arrhythmias in Defining Cardiac Dysfunction during Sepsis

To the Editor: We read with interest the article by Takasu and colleagues investigating cardiac and renal pathologic changes in patients who died with sepsis (1). We have two comments and two questions for the authors: The authors correctly point out that it is “difficult to know the extent of sepsis-induced myocardial depression” among their study subjects, who on average had normal ejection fractions and among whom only 13/38 (34%) required potent β-agonists (e.g., dobutamine or epinephrine). Circulatory failure from distributive shock requiring vasopressors may or may not occur in the setting of cardiac dysfunction. The study by Takasu and colleagues highlights the need for more clear definitions of “cardiac dysfunction” during sepsis. New-onset arrhythmias [particularly atrial fibrillation (AF)] during sepsis traditionally have not been considered signs of “cardiac dysfunction.” However, epidemiologic evidence suggests that new-onset AF represents an additional “organ failure” in patients with severe sepsis. For example, hospital mortality rates of patients with new-onset AF during sepsis are similar to patients without new-onset AF, but with one additional organ failure (2). We propose that future studies include dysfunction of the cardiac electrical system as evidence of “cardiac dysfunction during sepsis,” that is, serious arrhythmias such as AF, atrial flutter, ventricular tachycardia, or ventricular fibrillation. In regards specifically to the study by Takasu and colleagues, data from Table E4 in their online supplement shows that 6/38 (16%) of patients with sepsis had pre-existing AF and 1/38 (2.6%) developed new-onset AF. Was AF systematically ascertained by the investigators? The proportions of patients identified with AF during sepsis are much lower than previous reports. Finally, genomic and transcriptomic variation in connexin-43 previously has been demonstrated in patients and experimental models of AF (3). Although the tissue under examination in the present study was ventricular, rather than atrial, was there overlap between the seven patients with sepsis with connexin-43 abnormalities and the seven patients who had AF during sepsis? Specifically, might AF represent an alternative mechanism for the association between sepsis and connexin-43 abnormalities? Alternatively, could connexin-43 perturbations in sepsis be a mechanism predisposing susceptible patients to AF?

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Further insights into the underlying electrophysiological mechanisms for reduction of atrial fibrillation by ranolazine in an experimental model of chronic heart failure

Ranolazine (RAN) was reported to be effective and safe in converting atrial fibrillation (AF) to sinus rhythm by administration of a single dose ('pill in the pocket') to patients with structural heart disease. This study examines the underlying mechanisms for the antiarrhythmic benefit of RAN application in chronic heart failure (CHF). In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1 µM) and isoproterenol (1 µM) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of RAN (10 µM) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. RAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, RAN application moderately increased interatrial conduction time. RAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to development of atrial post-repolarization refractoriness and a moderate increase in conduction time. The described electrophysiological mechanisms remain preserved in the setting of CHF.

Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats

The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 μM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration-dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 μM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 μM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF.

Different properties of complex fractionated atrial electrograms during atrial fibrillation

The aim of the present study was to investigate various properties of complex fractionated atrial electrograms (CFAEs) in different models of atrial fibrillation. Fifteen dogs were divided into three groups (five dogs/group): group 1 (pacing-induced atrial fibrillation group), group 2 (100 mM Ach-induced atrial fibrillation group), group 3 (500 mM Ach-induced atrial fibrillation group). Five sites from the left atrium in each dog were used as recording sites. Electric stimulations were used to induce atrial fibrillation. Effective refractory period (ERP) of each recording site and atrial fibrillation inducibility index were obtained at baseline and following sustained atrial tachypacing for 4 h (group 1) or acetylcholine (Ach) application (groups 2 and 3). During the first induced atrial fibrillation, recording sites with CFAEs were identified and domain frequency of CFAE was obtained. ERPs decreased significantly compared to baseline in all groups (P < 0.001). There was no significant difference in decrements of ERPs at each site after pacing in group 1 (P = 0.646); in groups 2 and 3, significant differences were found in decrements of ERPs following Ach application when each site was compared (P < 0.05). Atrial fibrillation inducibility index increased in all groups compared to baseline (P < 0.05). During the first induced atrial fibrillation, CFAEs were recorded at all sites. There was no significant difference of domain frequencies in group 1 when each site was compared (P = 0.509), but significant differences in domain frequencies were found in groups 2 and 3 when each site was compared (P < 0.05). We identified that various characteristics of CFAEs may exist in different experimental models of atrial fibrillation. This may indicate different mechanisms of CFAEs.

Novel Strategy to Prevent Atrial Fibrosis and Fibrillation

To explore a novel strategy of preventing atrial fibrosis and atrial fibrillation (AF), we have established 3 appropriate experimental models of AF. Firstly, atrial fibrosis was induced by pressure overload by abdominal aortic constriction (AAC). AAC enhanced left atrial (LA) expression of monocyte chemoattractant protein-1. Scanning electron microscopy revealed that LA endothelial cells were irregularly hypertrophied, with disarrangement of lines of cells. Possible "arrested" leukocyte-derived cells were observed on the surface of LA endothelial cells. Treatment with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, resulted in attenuation of pressure overload-induced LA fibrosis. Secondly, LA fibrosis was induced by continuous infusion of angiotensin II (AII). Repeated whole-body hyperthermia led to the induction of heat shock protein (HSP) 72, which resulted in attenuation of AII-induced LA fibrosis. Thirdly, atrial fibrosis was induced by 5/6 nephrectomy as a model of AF associated with chronic kidney disease. Because the amount of nicotinamide adenine dinucleotide phosphate oxidase was increased and the potent antioxidant agent was effective, oxidative stress may be involved in the pathogenesis of LA fibrosis and enhanced AF vulnerability in this model. These observations suggest that inflammatory profibrotic processes are essential for the development of atrial fibrosis in these 3 models. Pioglitazone, induction of HSPs and antioxidant agent could be novel therapeutic approaches to preventing atrial fibrosis and AF.

Connexins and Atrial Fibrillation

Atrial fibrillation (AF) is an extremely common arrhythmia with important consequences and presently suboptimal therapeutic options.1 A great deal of research has been performed to understand the detailed mechanisms of AF, with the hope that a better appreciation of the fundamental determinants of arrhythmogenesis will lead to the development of novel, more successful treatment possibilities.2 Article see p 216 One aspect of AF pathophysiology that has elicited great interest has been changes in gap junction/connexin physiology. An important role for altered gap junction function and the potential importance of gap junctions as a therapeutic target for AF were first emphasized by Spach and Starmer over 15 years ago.3 Since that time, our understanding of gap junction physiology, biophysics, and molecular biology has increased enormously,4,5 as have studies on their role in AF pathogenesis and management.2 Gap junctions contain transmembrane ion-channel proteins called connexins (Figure,panel A). Connexons (containing 6 connexin molecules each) in the gap junctions of adjacent cardiomyocytes line up and attach, transferring ions or molecules <1 kDa freely between cells, coupling them electrically (Figure, panel B). Cardiac tissues express a variety of connexins, including connexin (Cx)40, Cx43, Cx45, Cx30.2/31.9, and Cx37,5 with all but Cx37 present in cardiomyocytes and the most important connexins in atrial tissue being Cx40 and Cx43. There is evidence that posttranslational modification, particularly connexin phosphorylation, is important in governing connexin localization and function.6 Figure. A , Connexons contain 6 connexins each, arranged in a circle. Connexins …