Atrial Electrophysiological Parameters Research Articles

Oroxin B Resembles Bisoprolol in Attenuating Beta1-Adrenergic Receptor Autoantibody-Induced Atrial Remodelling via the PTEN/AKT/mTOR Signalling Pathway.

Beta1-adrenergic receptor autoantibodies (β1-AAbs) promote atrial remodelling and ultimately lead to the development of atrial fibrillation (AF). Oroxin B is a natural flavonoid glycoside with a variety of biological activities, including anti-inflammatory and autophagy-promoting effects, and has therapeutic benefits for a variety of diseases. The aim of this study was to investigate the potential therapeutic role of Oroxin B in the development of β1-AAb-induced atrial fibrillation and to elucidate the underlying mechanisms involved. We established a rat model of β1-AAb-induced atrial fibrillation via active immunisation. The first stage was divided into three groups: the control group, the β1-AAb group and the β1-AAb + bisoprolol group. The second stage was divided into three groups: the control group, the β1-AAb group and the β1-AAb + Oroxin B group. Serum levels of β1-AAbs, atrial tissue levels of cyclic monophosphate (cAMP), atrial electrophysiological parameters, cardiac structure and function, mitochondrial structure, autophagy levels, cardiomyocyte apoptosis and myocardial fibrosis were examined. The results showed that bisoprolol, a β1-blocker, improved β1-AAb-induced atrial electrical remodelling, reduced atrial collagen deposition, ameliorated the increase in LAD and regulated the balance of autophagy and apoptosis in atrial myocytes through the PTEN/AKT/mTOR signalling pathway. Oroxin B, a PTEN agonist, can improve the impairment of autophagy homeostasis and apoptosis in atrial tissue by activating the PTEN/AKT/mTOR signalling pathway, thereby improving atrial structure and electrical remodelling. Moreover, Oroxin B may play a therapeutic role in β1AAb-induced atrial fibrillation. In conclusion, our results demonstrate the potential therapeutic role of Oroxin B in β1AAb-induced atrial fibrillation and the underlying mechanisms, suggesting that Oroxin B may be an effective antiarrhythmic medication.

P2X7 receptor inhibition prevents atrial fibrillation in rodent models of depression.

Depression, the most prevalent psychiatric disorder, is associated with the occurrence and development of atrial fibrillation (AF). P2X7 receptor (P2X7R) activation participates in the development of depression, but little attention has been given to its role in AF. This study was to investigate the effects of P2X7R on AF in depression models. Lipopolysaccharide (LPS) and chronic unpredictable stress (CUS) were carried out to induce depression in rodents. Behavioural assessments, atrial electrophysiological parameters, electrocardiogram (ECG) parameters, western blot, and histology were performed. Atrial fibrillation inducibility was increased in both LPS- and CUS-induced depression, along with the up-regulation of P2X7R in atria. CUS facilitated atrial fibrosis. CUS reduced heart rate variability (HRV) and increased the expression of TH and GAP43, representing autonomic dysfunction. Down-regulation of Nav1.5, Cav1.2, Kv1.5, Kv4.3, Cx40, and Cx43 in CUS indicated the abnormalities in ion channels. In addition, the expression levels of TLR4, P65, P-P65, NLRP3, ASC, caspase-1, and IL-1β were elevated in depression models. Pharmacological inhibitor (Brilliant Blue G, BBG) or genetic deficiency of P2X7R significantly mitigated depressive-like behaviours; ameliorated electrophysiological deterioration and autonomic dysfunction; improved ion channel expression and atrial fibrosis; and prevented atrial NLRP3 inflammasome activation in the pathophysiological process of AF in depression models. LPS or CUS induces AF and promotes P2X7R-dependent activation of NLRP3 inflammasome, whereas pharmacological P2X7R inhibition or P2X7R genetic deficiency prevents atrial remodelling without interrupting normal atrial physiological functions. Our results point to P2X7R as an important factor in the pathology of AF in depression.

TRPV2 inhibitor tranilast prevents atrial fibrillation in rat models of pulmonary hypertension

Atrial fibrillation (AF) is common in pulmonary hypertension (PH), whereas the mechanisms and treatments remain to be explored. TRPV2 regulates the structure and function of the cardiovascular system; however, little attention has been given to its role in AF. This study was to determine whether TRPV2 was involved in PH-induced AF and the effects of TRPV2 inhibitor tranilast on AF in rat models of PH. Monocrotaline (MCT) and SU5416/hypoxia (SuHx)-induced PH models were performed to detect atrial electrophysiological parameters. Daily tranilast (a TRPV2 inhibitor) or saline was given starting 1 day before PH establishment. PH increased the susceptibility to AF, with TRPV2 up-regulated in the right atria. Compared to PH rats, tranilast reduced AF inducibility and the prolongations of ERP and APD; mitigated cardiopulmonary remodeling and the increases in P-wave duration and P-R interval; partially reversed the down-regulation of ion channels such as Cav1.2, Nav1.5, Kv4.3, Kv4.2, Kv1.5, Kir2.1, Kir3.1, Kir3.4 as well as connexin (Cx) 40 and Cx43; improved right atrial (RA) fibrosis, enlargement, and myocardial hypertrophy; decreased the accumulation of inflammatory cells; down-regulated inflammatory indicators such as TNF-α, IL-1β, CXCL1, and CXCL2; and inhibited the activation of the PI3K-AKT-NF-κB signaling pathway. Our results reveal that TRPV2 participates in PH-induced AF, and TRPV2 inhibitor tranilast prevents PH-induced RA remodeling. TRPV2 might be a promising target for PH-induced AF.

Pinocembrin attenuates susceptibility to atrial fibrillation in rats with pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling that triggers fibrosis and excessive myocardium apoptosis, ultimately facilitating atrial fibrillation (AF). In various rat models, Pinocembrin has anti-fibrotic and anti-apoptotic effects, reducing arrhythmia vulnerability. However, whether pinocembrin alleviates to AF in a PAH model remains unclear. The experiment aims to investigate how pinocembrin affects AF susceptibility in PAH rats and the possible mechanisms involved. MethodsThe PAH model was induced by monocrotaline (MCT; i. p. 60 mg/kg). Concurrently, rats received pinocembrin (i.p.50 mg/kg) or saline. Hemodynamics parameters, electrocardiogram parameters, lung H.E. staining, atrial electrophysiological parameters, histology, Western blot, and TUNEL assay were detected. ResultsCompared to the control rats, MCT-induced PAH rats possessed prominently enhancive mPAP (mean pulmonary artery pressure), pulmonary vascular remodeling, AF inducibility, HRV, right atrial myocardial fibrosis, apoptosis, atrial ERP, APD, and P-wave duration. Additionally, there were lowered protein levels of Cav1.2, Kv4.2, Kv4.3, and connexin 40 (CX40) in the MCT group in right atrial tissue. However, pinocembrin reversed the above pathologies and alleviated the activity of the Rho A/ROCKs signaling pathway, including the expression of Rho A, ROCK1, ROCK2, and its downstream MYPT-1, LIMK2, BCL-2, BAX, cleaved-caspase3 in right atrial and HL-1 cells. ConclusionPresent data exhibited pinocembrin attenuated atrial electrical, ion-channel, and autonomic remodeling, diminished myocardial fibrosis and apoptosis levels, thereby reducing susceptibility to AF in the MCT-induced PAH rats. Furthermore, we found that pinocembrin exerted inhibitory action on the Rho A/ROCK signaling pathway, which may be potentially associated with its anti-AF effects.

Sympatho-vagal activation during obstructive respiratory events in pigs and blunted atrial arrhythmogenic effects by pharmacological IKACh-inhibition

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo nordisk foundation Background Obstructive sleep apnea (OSA) is associated with a sympatho-vagal activation which is suspected to create a complex substrate for atrial fibrillation (AF). Purpose In pigs, we investigated atrial arrhythmogenic consequences of simulated obstructive respiratory events by intermittent negative upper airway pressure (INAP) application and tested antiarrhythmic properties of an atria-specific IK,ACh-inhibitor. Methods In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 seconds, every 10 minutes, three times before (vehicle) and two times following infusion of an IK,ACh-inhibitor. P-wave, PQ-duration, atrial effective refractory periods (AERP) and left ventricular hemodynamic parameters (maximum upstroke velocity, minimal downslope velocity and systole duration) were acquired before (Pre-INAP), during (INAP) and after (Post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. Results During vehicle infusion, INAP transiently shortened AERP (Pre-INAP: 147±8ms vs. Post-INAP 105±12 ms; p=0.021) and increased AF-inducibility (Pre-INAP: 10±6% vs. Post-INAP 57±15%; p=0.018). Whereas p-wave duration remained stable, PQ-duration prolonged (Pre-INAP: 130±6ms vs. Post-INAP 142±7ms; p=0.03). Left ventricular maximum upstroke velocity increased (Pre-INAP: 1990±118 mmHg/s vs. Post-INAP 3980±704 mmHg/s; p=0.04), minimal downslope velocity decreased and systole duration shortened (Pre-INAP: 236±6 ms vs. Post-INAP 202±12 ms; p=0.04). The IK,ACh-inhibitor increased AERP (vehicle 147±8ms vs. IK,ACh-inhibitor 171±9ms; p=0.05) and sufficiently prevented INAP-associated AERP-shortening (Pre-INAP: 171±9ms vs. Post-INAP 180±9ms; p=0.219) and PQ-duration prolongation (Pre-INAP: 116±8ms vs. Post-INAP 113±7ms; p=0.76). INAP-induced changes of left ventricular maximum upstroke/minimal downslope velocity and systole duration remained unaffected in the presence of the IK,ACh-inhibitor. Conclusion During obstructive respiratory events simulated by INAP in pigs, left ventricular hemodynamic changes demonstrated elevated sympathetic tone, while atrial electrophysiological parameters resemble elevated parasympathetic tone at the same time. This was associated with increased AF-susceptibility. Pharmacological IK,ACh-inhibition blunted INAP-induced impairment of atrial electrophysiology without affecting left ventricular hemodynamic changes. Hence, pharmacological IKACh-inhibition may constitute a promising treatment strategy in AF-patients with OSA.

The SCN5A point mutation M1875T, associated with familial atrial fibrillation, causes a gain-of-function effect of the cardiac Nav1.5 channel in atrial cardiomyocytes

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Leducq Foundation Background The point mutation M1875T in the SCN5A gene, which encodes the pore-forming α-subunit of the cardiac voltage-gated Na+ channel Nav1.5, has been associated with familial atrial fibrillation (AF), but its effects on atrial cardiomyocyte electrophysiology is unclear. Aim To investigate the effect of the point mutation M1875T on atrial electrophysiological parameters. Methods In a novel heterozygous knock-in murine model (Scn5a-M1875T+/-), whole-cell patch clamp electrophysiology was used to investigate Na+ currents in left atrial (LA) cardiomyocytes isolated from hearts of young adult mice (10-16 weeks). LA microelectrode and optical mapping recordings were used to study action potential (AP) characteristics. Cardiac size and function were measured by transthoracic echocardiography. Atrial Scn5a gene and Nav1.5 protein expression were assessed by Rt-PCR and Western blot. Results The Na+ current was increased in cardiomyocytes isolated from Scn5a-M1875T+/- LA (wildtype (WT) -22.7 ± 0.9 pA/pF (N = 14, n = 115); Scn5a-M1875T+/- -28.3 ± 1.1 pA/pF (N = 15, n = 117)). Scn5a-M1875T+/- intact isolated superfused LA had an elevated AP amplitude (100 ms pacing cycle length (PCL): WT 86.4 ± 0.9 mV (N = 8, n = 24); Scn5a-M1875T+/- 91.2 ± 0.7 mV (N = 8, n = 25)) and a faster peak upstroke velocity (100 ms PCL: WT 127.98 ± 3.28 mV/ms; Scn5a-M1875T+/- 142.80 ± 3.98 mV/ms). AP duration (APD) was not different apart from a small APD shortening at slow rates. Echocardiography revealed no difference in size and function at the age of investigation. Atrial Scn5a gene and Nav1.5 protein expression were comparable. When challenged with flecainide (1 µM), Scn5a-M1875T+/- LA showed less conduction slowing than WT (100 ms PCL: WT -10.43 ± 1.27 cm/s (N = 12); Scn5a-M1875T+/- -6.10 ± 1.34 cm/s (N = 12)). 5 µM flecainide caused significant increase in WT refractoriness (7/12 atria lost 1:1 capture at PCL ≤ 120 ms) compared to Scn5a-M1875T+/- (1/12). Conclusion(s): SCN5A point mutation M1875T increases the Na+ current in atrial cardiomyocytes and intact atria, leading to a faster AP upstroke and an attenuated response to flecainide. Abstract Figure 1: Current-Voltage relationship

Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation

There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity. The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats. Electrode patches were implanted on the atrial epicardium of 8 Dutch milk goats. Experiments were performed at baseline and after 2 and 14 days of electrically maintained AF. Several electrophysiological parameters and AF episode duration were measured during infusion of vehicle and different doses of ranolazine (target plasma levels 4, 8, and 16 μM, respectively). The highest dose of ranolazine significantly prolonged atrial effective refractory period and decreased atrial conduction velocity at baseline and after 2 days of AF. After 2 weeks of AF, ranolazine prolonged the p5 and p50 of AF cycle length distribution in a dose-dependent manner but was not effective in restoring sinus rhythm. No adverse ventricular arrhythmic events (eg, premature ventricular beats or signs of hemodynamic instability) were observed during infusion of ranolazine at any point in the study. The lowest investigated dose of ranolazine, which is expected to block both late INa and atrial peak INa, had no effect on the investigated electrophysiological parameters. The highest dose affected both atrial and ventricular electrophysiological parameters at different stages of AF-induced remodeling but was not efficacious in cardioverting AF to sinus rhythm in a goat model of lone AF.

Genetic background, sex, age and pacing cycle length affect left atrial electrophysiology in Langendorff-perfused isolated murine hearts

Abstract Background Studying cardiac electrophysiology in isolated perfused beating murine hearts is a well-established method. The ranges of normal values for left atrial (LA) action potential durations (LA-APD), activation times (LA-AT) and effective refractory periods (atrial ERP) in murine wildtype (WT) are not well known. Purpose This study aimed to establish reference values for LA-APD, LA-AT and atrial ERP and to identify the influence of genetic background, sex and age on these electrophysiological parameters in WT mice. Method We combined results from isolated beating heart Langendorff experiments carried out in WT mice between 2005 and 2019 using an octopolar catheter inserted into the right atrium and a monophasic action potential electrode recording from the LA epicardium. Electrophysiological parameters (LA-APD at 50%, 70%, 90% repolarization (APD50, APD70, APD90), LA-AT and atrial ERP) at different pacing cycle lengths (PCL) were summarized. We analysed effects of PCL, genetic background, age, gender, heart weight to body weight ratio (HW/BW), LA weight to body weight ratio (LAW/BW) as well as coronary flow and temperature as experimental conditions. Results Electrophysiological parameters from 222 isolated hearts (114 female, mean age 6.6±0.25 months, range 2.47–17.7 months) of different backgrounds (77 C57BL/6, 23 FVB/N, 33 MF1, 69 129/Sv and 20 Swiss agouti) were combined. Coronary flow rate, flow temperature and start of isolation to cannulation time were constant experimental conditions over the timespan of experiments. LA-APD was longer while LA-AT decreased with longer PCL throughout all genetic backgrounds (Figure 1A). Genetic background showed strong effects on all electrophysiological parameters. LA-APD70 and atrial ERP were significantly shorter in Swiss agouti background compared to others. LA-APD70 was also significantly prolonged in 129/Sv background compared to MF1 (Figure 1B). LA activation was delayed in 129/Sv compared to other backgrounds (Figure 1C). Atrial ERP was longer in FVB/N compared to other backgrounds. Atrial ERP was also significantly prolonged (+ 3.4 ms, + 13.5%) in female mice compared to males (Figure 1D). Age effects were compared in groups. Atrial ERP was significantly longer in mice younger than 3 months compared to older mice (Figure 1E). Conclusion This dataset summarises left atrial electrophysiological parameters in the beating mouse heart and can serve as a reference for design and interpretation of electrophysiological experiments in murine models of commonly used genetic backgrounds. We demonstrate that PCL, genetic background, age and gender affect atrial electrophysiological parameters. Awareness of these will support successful experimental design. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) to LF and PK, Deutsche Forschungsgemeinschaft DFG FA413, British Heart Foundation (FS/13/43/30324 to LF and PK; AA/18/2/34218 to LF and PK).The Institute of Cardiovascular Sciences has received the British Heart Foundation (BHF) Accelerator Award (AA/18/2/34218). JO has received financial support for abroad studies within his scholarship of the Studienstiftung des deutschen Volkes (German Academic Scholarship Foundation).

1272Effect of age, genetic background and experimental conditions on left atrial monophasic action potential duration, effective refractory period and activation time in Langendorff-perfused murine hearts

Abstract Funding Acknowledgements Supported by EU [CATCH ME] 633196, British Heart Foundation FS/13/43/30324, AA/18/2/34218 LF, PK, DFG FA413 LF, Studienstiftung to JO. Background Studying cardiac electrophysiology in isolated perfused beating murine hearts is a well-established method. The range of normal values for left atrial action potential durations (LA-APD), activation times (LA-AT) and effective refractory periods (atrial ERP) in murine wildtype (WT) is not well known. Purpose This study aimed to establish reference values for LA-APD, LA-AT and atrial ERP and to identify factors that influence these electrophysiological parameters in wildtype (WT) mice. Method We combined results from isolated beating heart Langendorff experiments carried out in WT between 2005 and 2019 using an octopolar catheter inserted into the right atrium and a monophasic action potential electrode recording from the LA epicardium. Electrophysiological parameters (LA-APD at 50%, 70%, 90% repolarization (APD50, APD70, APD90), LA-AT and atrial ERP) at different pacing cycle lengths (PCL) were summarized. We analyzed effects of PCL, genetic background, age, gender, heart weight to body weight ratio (HW/BW), LA weight to body weight ratio (LAW/BW) as well as coronary flow and temperature as experimental conditions. Results Electrophysiological parameters from 222 isolated hearts (114 female, mean age 6.6 ± 0.25 months, range 2.47-17.7 months) of different backgrounds (77 C57BL/6, 23 FVB/N, 33 MF1, 69 129/Sv and 20 Swiss agouti) were combined. Coronary flow rate, flow temperature and start of isolation to cannulation time were constant experimental conditions over the timespan of experiments. LA-APD was longer while LA-AT decreased with longer PCL throughout all genetic backgrounds (Figure 1A). Genetic background showed strong effects on all electrophysiological parameters. LA activation was delayed in 129/Sv compared to other backgrounds (Figure 1D). LA-APD70 and atrial ERP were significantly shorter in Swiss agouti background compared to others. LA-APD70 was also significantly prolonged in 129/Sv background compared to MF1 (Figure 1C). Atrial ERP was longer in FVB/N compared to other backgrounds. Age effects were compared in groups. Atrial ERP was significantly longer in mice ≤ 3 months compared to all older mice. Atrial ERP was also significantly prolonged (+ 3.4ms, + 13.5%) in female mice compared to males (Figure 1B). Conclusion This dataset summarizes left atrial electrophysiological parameters in the beating mouse heart and can serve as a reference for design and interpretation of electrophysiological experiments in murine models of commonly used genetic backgrounds. We confirm that cycle length, genetic background, age and gender affect atrial electrophysiological parameters. Awareness of these will support successful experimental design. Abstract Figure 1

Interactions between metabolism regulator adiponectin and intrinsic cardiac autonomic nervous system: A potential treatment target for atrial fibrillation

BackgroundPrevious studies indicated that inhibiting the cardiac autonomic nervous system (CANS) suppressed atrial fibrillation (AF). Clinical research revealed serum adiponectin (APN) exerted a beneficial influence on sympathetic and vagal tone in patients with type 2 diabetes. However, the effects of APN on CANS is unknown. This study aims to investigate whether APN could regulate CANS and suppress rapid atrial pacing (RAP)-induced AF. MethodsEighteen beagles were divided into the control group (saline plus sham RAP, N = 6), the RAP group (saline plus RAP, N = 6) and the APN + RAP group (APN plus RAP, N = 6). APN (10 μg, 0.1 μg/μL) or saline was microinjected into 4 major ganglionated plexi (GP) prior to RAP. Atrial electrophysiological parameters, anterior right GP (ARGP) function, neural activity and GP tissues were detected. ResultsCompared with the control treatment, RAP shortened effective refractory period (ERP) values at all sites and increased cumulative window of vulnerability (ΣWOV), ARGP function and neural activity, whereas APN injection reversed these changes. Mechanistically, APN ameliorated RAP-induced inflammatory response and down-regulated the expression of c-fos protein and nerve growth factor. Moreover, the APN receptors 1 and APN receptors 2 were detected both in neurons and in non-neuronal cells. APN pretreatment activated downstream adenosine monophosphate-activated protein kinase (AMPK) signaling, inhibited nuclear factor-kappa B signaling and promoted macrophage phenotype switching from proinflammatory to anti-inflammatory state. ConclusionsThis study demonstrates that administration of APN into GP can suppress RAP-induced AF by regulating the CANS. APN signaling may provide a potential therapeutic target to AF.

Chronic inhibition of the sigma-1 receptor exacerbates atrial fibrillation susceptibility in rats by promoting atrial remodeling

AimsThis study aimed to evaluate the effects of the sigma-1 receptor (S1R) on atrial fibrillation (AF) susceptibility in rats. Main methodsRats were randomly assigned into three groups for intraperitoneal treatment with saline (CTL group), BD1047 (an antagonist of the S1R, BD group) or BD1047 plus fluvoxamine (an agonist of the S1R, BD + F group) for 4 weeks. The heart rate variability (HRV) and atrial electrophysiological parameters were measured via the PowerLab system and analyzed by LabChart 8.0 software. Atrial histology was determined with Masson staining. The protein levels of connexin (Cx) 40, Cav1.2, S1R, eNOS, p-eNOS, and p-AKT were detected by western blot assays. Key findingsOur results showed that BD1047 significantly shortened the atrial effective refractory period (ERP) and action potential duration (APD), increased AF inducibility and duration, augmented sympathetic activity, depressed parasympathetic activity, and reduced heart rate variability (HRV) compared with the CTL group. Masson staining also showed a significant increase in atrial fibrosis in the BD group. Furthermore, the expressions of S1R, Cx40, Cav1.2, p-eNOS, and p-AKT were dramatically reduced in the BD group compared with the CTL group (all P < 0.01). However, fluvoxamine administration mitigated most of the abovementioned alterations. SignificanceOur findings indicated that S1R inhibition contributed to atrial electrical remodeling, cardiac autonomic remodeling and atrial fibrosis, which could be attenuated by fluvoxamine, thus providing new insights into the relationship between the S1R and AF.

Qiliqiangxin attenuates atrial structural remodeling in prolonged pacing-induced atrial fibrillation in rabbits.

Qiliqiangxin (QL) can attenuate myocardial remodeling and improve cardiac function in some cardiac diseases, including heart failure and hypertension. This study was to explore the effects and mechanism of QL on atrial structural remodeling in atrial fibrillation (AF). Twenty-one rabbits were randomly divided into a sham-operation group, pacing group (pacing with 600 beats per minute for 4weeks), and treatment group (2.5g/kg/day). Before pacing, the rabbits received QL-administered p.o. for 1week. We measured atrial electrophysiological parameters in all groups to evaluate AF inducibility and the atrial effective refractory period (AERP). Echocardiography evaluated cardiac function and structure. TUNEL detection, hematoxylin and eosin (HE) staining, and Masson's trichrome staining were performed. Immunohistochemistry and western blotting (WB) were used to detect alterations in calcium channel L-type dihydropyridine receptor α2 subunit (DHPR) and fibrosis-related regulatory factors. AF inducibility was markedly decreased after QL treatment. Furthermore, we found that AERP and DHPR were reduced significantly in pacing rabbits compared with sham rabbits; treatment with QL increased DHPR and AERP compared to the pacing group. The QL group showed significantly decreased mast cell density and improved atrial ejection fraction values compared with the pacing group. Moreover, QL decreased interventricular septum thickness (IVSd) and left ventricular end-diastolic diameter (LVEDD). Compared with the sham group, the levels of TGFβ1 and P-smad2/3 were significantly upregulated in the pacing group. QL reduced TGF-β1 and P-smad2/3 levels and downstream fibrosis-related factors. Our study demonstrated that QL treatment attenuates atrial structural remodeling potentially by inhibiting TGF-β1/P-smad2/3 signaling pathway.

Resveratrol prevents atrial fibrillation by inhibiting atrial structural and metabolic remodeling in collagen-induced arthritis rats.

Rheumatoid arthritis (RA) causes atrial remodeling that induces the occurrence and maintenance of atrial fibrillation (AF). In this study, we explored the influence of RA on atrial fibrillation and the potential therapeutic effects of resveratrol in a rat model. The following three groups of female Wistar rats (8weeksold) were used in this study: control, collagen-induced arthritis (CIA), and resveratrol. Rats in the CIA and resveratrol groups were injected twice with type II collagen in Freund's incomplete adjuvant. Three weeks after the second injection, resveratrol (10mgkg-1day-1) was administered for 4weeks. Subsequently, atrial electrophysiological parameters were measured. Levels of inflammatory factors in the atria and serum were measured. Atrial histopathological changes were assessed using microscopy, and cardiomyocyte apoptosis and fibrosis were assessed using TUNEL and Masson's staining. Apoptosis-related and fibrosis-related proteins were assessed using Western blotting. Atrial adenosine triphosphate (ATP) and free fatty acid (FFA) levels were tested using ELISA. Glycogen accumulation and metabolism-related protein expression were assessed. AF inducibility and duration were markedly increased in CIA rats and were reduced by resveratrol. CIA also increased the atrial and serum IL-6 and TNF-a levels and induced atrial apoptosis and fibrosis, which were attenuated by resveratrol. Moreover, CIA induced the impairment of atrial energy metabolism by inhibiting the AMPK/PGC-1α pathway, which was reversed by resveratrol. Resveratrol protects against RA-induced atrial structural and metabolic remodeling, which may provide a new potential therapeutic treatment for RA-related AF.

Comorbid Obesity and Metabolic Syndrome Add to the Atrial Arrhythmogenic Phenotype in Hypertensive Rats

Introduction: Besides hypertension alone, comorbid obesity and the metabolic syndrome are emerging risk factors for atrial fibrillation (AF). This study sought to delineate the development of global electrophysiological and structural substrate for AF in hypertension with and without obesity and metabolic syndrome. Methods: We compared an obese spontaneously hypertensive rat model (SHR-ob, n = 10) with lean spontaneously hypertensive rats (SHR-lean, n = 10) and normotensive controls (Ctr, n = 10). Left atrial (LA) emptying function (magnetic resonance imaging) and atrial electrophysiological parameters were measured before the hearts were harvested for histological and biochemical analysis. Results: At the age of 39 weeks, SHR-ob, but not SHR-lean and Ctr, showed impaired glucose tolerance and increased body-weight together with dyslipidaemia. Systolic blood pressure was similarly increased in SHR-lean and SHR-ob when compared to Ctr (252 ± 7 and 242 ± 7 mmHg (n.s.), vs. 155 ± 2 mmHg, p < 0.01 for both). Compared to Ctr, impairment of LA emptying function, rise in total atrial activation time and regions of slow conduction as well as prolongation of inducible AF-duration were more pronounced in SHR-ob than in SHR-lean. Histological and biochemical examinations revealed a more pronounced increase in LA fibrosis and LA gene expression of profibrotic markers like osteopontin, connective tissue growth factor (cTGF) and transforming growth factor (TGF)-β1 and advanced glycation endproduct content in SHR-ob compared to SHR-lean. Conclusions: In addition to hypertension alone, comorbid obesity and metabolic syndrome adds to the atrial arrhythmogenic phenotype by impaired LA-emptying function, conduction abnormalities, interstitial atrial fibrosis, increased profibrotic gene expression and increased propensity for AF.

EXAMINATION OF ELECTROPHYSIOLOGICAL PARAMETERS OF THE ATRIUMS IN PATIENTS WITH LONG-TERM PERSISTENT FORM OF ATRIAL FIBRILLATION AND VALVULAR HEART DISEASE

The study objective is to examine electrophysiological parameters of atrial myocardium, characteristics of atrioventricular conduction, and potential factors affecting recurrent atrial fibrillation (AF) in patients with persistent and long-term persistent forms of AF prior to the Labirynth IIIB surgery with single-step correction of valvular heart disease. Materials and methods . The study included 100 adults (48 men, 52 women) with persistent and long-term persistent forms of AF and different valvular heart diseases. Mean patient age was 59 years. Mean AF duration was 4 years. All patients were prescribed antiarrhythmic therapy but it proved ineffective. In 15 % of patients, restoration of the sinus rhythm was attempted through electrical cardioversion but long-term control of the sinus rhythm wasn’t achieved. All patients were diagnosed with organic pathology of the mitral valve. Also, in 80 % of patients, relative insufficiency of the tricuspid valve was detected. Chronic heart failure functional class per NYHA was III. Size of the left atrium was 5 cm, mean left ventricular ejection fraction was 61 %. All patients underwent electrical cardioversion. After successful restoration of the sinus rhythm, endocardial electrophysiology study (EES) of the heart was performed. Then, correction of valvular pathologies and the Labyrinth IIIB surgery were performed. Results. Examination of refractoriness of different parts of the atriums has shown that effective refractory period (ERP) of the atrioventricular node was minimal compared to other parts of the atriums. Maximal ERP duration was observed in the upper part of the right atrium. Therefore, in patients with long history of AF, heterogeneity of atrial myocardium ERP duration is observed. In 17 % of patients, atrial vulnerability was detected. The area of atrial vulnerability was always associated with ERP. Its duration in patients with atrial vulnerability was significantly higher. Conclusion. Long-term mitral valve incompetence and persistent AF lead to anatomical and electrophysiological remodeling of the atriums, which manifests through increased volume of the left atrium, as well as increased duration of intra-atrial conduction and heterogeneity of refractory periods. EES allows to evaluate these functions of the atrioventricular conduction system and atrial electrophysiological parameters: detect aberrations in conduction through atrial myocardium, dispersion of its refractoriness, and the area of atrial vulnerability. These factors can serve as predictors of AF recurrence.

Cathepsin A mediates susceptibility to atrial tachyarrhythmia and impairment of atrial emptying function in Zucker diabetic fatty rats

Type 2 diabetes (T2D) is an independent risk factor for atrial fibrillation (AF) and stroke. The serine protease cathepsin A (CatA) is up-regulated in diabetes and plays an important role in the degradation of extracellular peptides. This study sought to delineate the role of CatA for the development of atrial remodelling under diabetic conditions. Zucker Diabetic Fatty rats (ZDF) were treated with vehicle (n = 20) or CatA-inhibitor (SAR; 50 mg/kg; n = 20), and compared with age-matched non-diabetic littermates (Ctr, n = 20). Left-atrial (LA) emptying function [magnetic resonance imaging (MRI)] and atrial electrophysiological parameters were measured before sacrifice for histological and biochemical analysis. The impact of enhanced cardiac CatA expression on atrial remodelling was determined using CatA-transgenic mice. At the age of 9.5 months, atrial tissues of ZDF rats showed increased CatA gene expression and CatA-activity, along with increased AF-susceptibility and impaired LA-emptying function. CatA-inhibition reduced CatA-activity in ZDF comparable to Ctr values and decreased LA-fibrosis formation and connexin 43 lateralization. This was associated with shorter median duration of LA-tachyarrhythmia (12.0 ± 1.7 vs. 1.2 ± 0.47 s, P < 0.01) induced by burst pacing and diminished regions of slow conduction. Cardiac MRI revealed better LA-emptying function parameters (active per cent emptying: 29 ± 1 vs. 23 ± 2%, P < 0.01) after CatA-inhibition. CatA-inhibition reduced LA bradykinin-degrading activity in ZDF. Transgenic mice overexpressing CatA demonstrated enhanced atrial fibrosis formation and increased AF-susceptibility. T2D leads to arrhythmogenic atrial remodelling in ZDF rats. CatA-inhibition reduces LA bradykinin-degrading activity in ZDF and suppresses the development of atrial structural changes and AF-promotion, implicating CatA as an important mediator for AF-substrate in T2D.

THE EFFECT OF ALDOSTERONE ANTAGONISTS ON THE ELECTROPHYSIOLOGICAL PARAMETERS IN RECURRENCE ATRIAL FIBRILLATION

Purpose: to investigate the effect of mineralocorticoid receptor antagonists on atrial electrophysiological parameters and frequency of AF episodes in recurrence AF and left ventricular diastolic dysfunction. Material and methods: prospective cohort study included 89 patients with recurrence non-valvular AF and left ventricular diastolic dysfunction who had sinus rhythm at baseline. All patients received ACE inhibitors, β-blockers, statins, antithrombotic and antiarrhythmic drugs and were randomly assigned to either standard therapy only (Control group, 46 patients) or mineralocorticoid receptor antagonists spironolactone 25 mg titrated to 50 mg (SPRL group, 43 patients) added to standard treatment. At baseline and after 6 months of treatment P-wave duration and dispersion of standard electrocardiogram (ECG), P-wave signal-averaged ECG parameters (total filtered P-wave duration (FiP) and a root-mean-squared voltage of the terminal 20 ms (RMS-20) and atrial late potentials (ALP) were evaluated. The primary endpoint of the study was AF recurrence. Results: at baseline there were no significant differences between groups. After 6 months of treatment significant reduction in P-wave dispersion were found in SPRL group. FiP improved significantly in both groups, but more in the SPRL group, RMS-20 increased only in the SPRL group. At baseline ALP was detected in 38 (82.6%) patients in Control group and in 36 (83.7%) of SPRL group (χ2 = 0.02, p = 0.887). After 6 months the ALP rate was significantly decreased in SPRL group (56.1%, χ2 = 6.4, p = 0.011 compared to baseline) but remained high in Control (76.0%, χ2 = 0.27, p = 0.6). AF recurrences were documented in 33 (71.7%, 95% CI 57.6-84.0%) patients in Control group and in 21 (48.8%, 95% CI 33.7-64.0%) in SPRL group (χ2 = 3.97, p = 0.046). Additional spironolactone intake was associated with 22.9% (95% CI 2.6-40.8%, p = 0,048) risk reduction of AF recurrence. Summary: application of spironolactone for 6 months additionally to standard therapy in patients with recurrent AF and left ventricular diastolic dysfunction leads to significant improvement in the atrial electrophysiological parameters and decrease in AF recurrence.

Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements.

Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. Ex vivo perfusion study: Isolated guinea pig hearts were perfused with modified Krebs-Henseleit (K-H) buffer with or without ZA 0.07 mg/kg/L (each n = 6). In ZA-perfused hearts, atrial action potential at 90% repolarization (APD90 ) decreased more from baseline than in controls (-23.2% ± -5.1% vs. -2.1% ± -8.1%, P < 0 .0001), as did APD30 (-28.8% ± -3.8% vs. -2.1% ± -2.1%, P < 0.0001). In vivo dose-response study: Guinea pigs underwent intraperitoneal injections every 2 weeks in 1 of 4 groups (each n = 8): ZA 0.007 mg/kg (low-dose), ZA 0.07 mg/kg (medium-dose), ZA 0.7 mg/kg (high-dose), or placebo. Hearts were excised at 8 weeks and perfused with modified K-H. Atrial effective refractory period (ERP) was lower with medium- and high-dose ZA versus placebo (P = 0.004). Atrial APD30 was lower with high-dose ZA versus placebo, low and medium doses (P < 0.001). Canine ECG study: Mature female beagles received intravenous ZA 0.067 mg/kg or saline (placebo; each n = 6) every 2 weeks for 12 weeks. P wave dispersion was greater in the ZA group (7.7 ± 3.7 vs. 3.4 ± 2.6 ms, P = 0.04). There were no significant differences in P wave index, maximum or minimum P wave duration, or PR interval. ZA shortens left atrial APD and ERP and increases P wave dispersion.

Rosiglitazone attenuates atrial structural remodeling and atrial fibrillation promotion in alloxan-induced diabetic rabbits.

The pleiotropic effects of glitazones may favorably affect atrial remodeling. We sought to investigate the effects of peroxisome proliferator-activated receptor-γ (PPAR-γ) activator rosiglitazone on atrial structural remodeling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits. Twenty alloxan-induced diabetic rabbits were randomly divided into two groups (10 animals in each group), namely the diabetic rosiglitazone group (treated with rosiglitazone 2mg/day/kg for 4weeks) and the nontreated diabetic group, while 10 additional healthy rabbits served as controls. Moreover, isolated Langendorff-perfused rabbit hearts were used to evaluate atrial electrophysiological parameters and vulnerability to AF, examined by burst pacing. Histological examination was also performed, whereas plasma oxidative stress and inflammatory biomarkers were measured. The duration of induced AF was significantly prolonged in the alloxan-induced diabetic rabbits compared with controls (1.6±0.4s vs. 0 s; P<0.05). Rosiglitazone treatment significantly reduced the duration of induced AF in the treated rabbits (1.6±0.4s vs. 1.2±0.05 s; P<0.05). Moreover, rosiglitazone attenuated atrial structural remodeling reducing the interatrial activation time (35.4±12.1ms vs. 24.2±10.8ms, P<0.05; control 23.3±10.4ms) and the atrial interstitial fibrosis as well (collagen volume fraction: 5.6±3.9% vs. 2.4±2.1%, P<0.05; control 1.6±0.8%). Rosiglitazone increased plasma superoxide dismutase (SOD) activity and, on the other hand, decreased malondialdehyde (MDA), hs-C-reactive protein, and tumor necrosis factor-α levels. Rosiglitazone attenuates arrhythmogenic atrial structural remodeling and AF promotion in alloxan-induced diabetic rabbits. Also, it seems to modulate oxidative stress and inflammation in this experimental model.

O137 Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits

Introduction: Due to anti-inflammatory properties of pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-g activator, it might exert beneficial effects on diabetesrelated atrial remodeling. Objectives: We aimed to investigate the potential effects of pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-g activator, on atrial remodeling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits. Methods: 72 alloxan-induced diabetic rabbits were randomly divided into three groups (n1⁄424 for each): diabetic pioglitazone treatment A group (DPA group, 4mg/day/kg), diabetic pioglitazone treatment B group (DPB group, 8mg/day/kg) and diabetic group (DM group), 24 healthy rabbits served as controls. 8 rabbits in each group were respectively used to electrophysiological and histological study, patch-clamp study and western blotting analysis. 8 rabbits in each groupweremonitored hemodynamics and recorded SBP, DBP and LVEDP and underwent transthoracic echocardiographic examination. After 8-week treatment, isolated Langendorff perfused rabbit hearts were used to evaluate atrial electrophysiological parameters and vulnerability to AF which examined by burst and S1S2 pacing. CVF was calculated by Sirius-Red (SR) staining.Whole-cell patch-clamp technique was used tomeasure APD and atrial ionic currents (ICaL and INa). Western-blot analysis was applied to assess atrial protein expression of ERK2, pERK, TGFb1, TLR4, NF-kB p50 and HSP70 in left atrial tissue. Results: LAD, IVST and PWT were significantly increased in DM group compared with controls, which were markly reduced by pioglitazone. SBP and DBP of DPI group were significantly lower than DM group (P<0.05). IACT and AERPD were prolonged and AF inducibility was increased in DM group (6/8 vs. 1/8, P<0.05) compared with controls, which were markly reduced by pioglitazone. Pioglitazone attenuated atrial structural remodeling, with significant reductions in CVF. APD90 and APD50 were prolonged in DM group (P<0.05 vs. control), the densities of INa were reduced and the densities of ICaL were increased in DM group (P<0.01 vs. control), which were attenuated by pioglitazone. Western-blot analysis revealed DM increased expression of pERK, TGF-b1, TLR4, NF-kB p50 and HSP70, which were reduced by pioglitazone. Conclusion: Pioglitazone prevented DM-related arrhythmogenic atrial remodeling and reduced vulnerability to AF, which may be due to its anti-inflammatory and anti-oxidative characteristics. Disclosure of Interest: None Declared