Substrate For Atrial Fibrillation Research Articles

Atrial Myxoma, the Substrate of Atrial Fibrillation, Accompanied by Thrombocytopenia - Perspectives for the Anticoagulation Option and a Future Surgery Intervention

Abstract Atrial myxomas are common benign tumors localized in the left atrium (85%). The diagnosis is often made during routine examination due to the fact that they are usually asymptomatic. Sometimes the complications of these benign tumors, consisting in embolic events and obstructive valvular disfunction, may be alarm signs that reveal the underlying pathological condition. We report the case of a 63-years-old female presenting with non-specific symptoms, the echocardiography was the one that showed the left atrial mass. The particularity that made this case special was the fact that the anticoagulation indication for the atrial fibrillation discovered on the ECG was correlated with the presence of the thrombocytopenia, so the final decision was to postpone it till the surgery. After the removal of the atrial tumor the sinusal rhythm was restored and the combination of beta-blockers and antiplatelet was the best therapeutic choice.

Histone deacetylase inhibition attenuates atrial arrhythmogenesis in sterile pericarditis

Cardiac surgery is complicated with atrial fibrillation (AF). Histone deacetylase (HDAC) inhibition reduces AF occurrence. In pericarditis, HDAC inhibition may modulate AF trigger and substrate. We recorded electrocardiograms in control and pericardiotomic (op) rabbits without and with an intraperitoneal injection of MPT0E014 (HDAC inhibitor). Conventional microelectrodes recorded action potentials (APs) in pulmonary veins (PVs), the right and left atrium (LA). Masson's trichrome was used to identify collagen fibers in PVs and the LA. Electrocardiograms showed frequent atrial premature contractions in op rabbits, but not in the other 3 groups. The beating rates in PVs and opPVs were decreased by MPT0E014 treatment. Spontaneous burst firings occurred in opPVs (36.4%), but not in control PVs. H2O2 induced greater burst firings in opPVs (72.7%) than in control PVs (11.1%), MPT0E014-treated PVs (16.7%), and MPT0E014-treated opPVs (12.5%). The AP duration at a repolarization extent of 90% (APD90) was shorter in the opLA than that in the control LA. In the presence of isoproterenol (1 μM), rapid atrial pacing (RAP, 20 Hz) induced a higher incidence of burst firings in the opLA (90%) than in the other groups. In contrast, acetylcholine (5 mM) and RAP induced a lower incidence of burst firing in the MPT0E014-treated LA (33.3%) than in the other groups. Fibrosis prevailed in opPVs and the opLA compared to the respective control PVs and LA, which was attenuated in those that received MPT0E014. In conclusion, a pericardiotomy increased fibrosis and arrhythmogenesis in PVs and the LA, which were prevented by HDAC inhibition.

Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation

Epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), but the underlying mechanisms remain to be fully elucidated. The purpose of this study was to examine, using human left atrial appendage (LAA) samples, the interactive relationship between the EAT profile and atrial myocardial fibrosis through histologic and biochemical analyses. LAA samples were obtained from 59 consecutive AF patients during cardiovascular surgery. In histologic analysis, adipose tissue, atrial myocardial fibrosis, EAT fibrosis, macrophage infiltration, and matrix metalloproteinase-2 and hypoxia-inducible factor-1α (Hif-1α) expression were evaluated in LAA sections. In biochemical analysis, proinflammatory/fibrotic proteins in EAT, total collagen in left atrial (LA) myocardium, angiopoietin-like protein-2 (Angptl2)-related proteins in EAT, and proinflammatory/fibrotic proteins in serum were evaluated. Histology revealed that the severity of fibrotic remodeling of EAT was associated with LA myocardial fibrosis. Immunohistochemical and electron microscopic findings revealed that fibrotic remodeling of EAT was associated with infiltration of macrophages and myofibroblasts. Protein concentration analysis demonstrated that the total collagen in the LA myocardium was positively correlated with proinflammatory and profibrotic cytokines/chemokines, including interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor-α, vascular endothelial growth factor, and matrix metalloproteinase-2 and matrix metalloproteinase-9 in EAT. The proinflammatory and profibrotic cytokines/chemokines in EAT and the total collagen in the LA were also positively correlated with Angptl2 in EAT. Our study demonstrated that fibrotic remodeling and cytokines/chemokines in peri-LA EAT were associated with atrial myocardial fibrosis as a substrate of AF. Our results also suggested that overexpression of Hif-1α and Angptl2 may be involved in these processes.

Levosimendan differentially modulates electrophysiological activities of sinoatrial nodes, pulmonary veins, and the left and right atria.

Calcium overload increases the risk of atrial fibrillation (AF). Levosimendan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase [PDE] III inhibitor), and glibenclamide (an ATP-sensitive potassium channel [KATP ] inhibitor). Levosimendan (0.03, 0.1, 0.3, and 1 μM) significantly increased spontaneous rates from 2.1 ± 0.2 to 2.5 ± 0.2, 2.5 ± 0.2, 2.5 ± 0.1, and 2.7 ± 0.2Hz, respectively, in PVs (n=10), but had no effects on denudated PVs (n=9). Additionally, levosimendan significantly induced burst firing and/or triggered beats in intact PVs, but not in denudated PVs. In contrast, levosimendan at 0.3 and 1 μM increased the SAN spontaneous rate. In the presence of milrinone (10 μM), levosimendan (1 μM) did not increase the PV spontaneous activity. Moreover, glibenclamide (100 μM) prevented acceleration of the levosimendan-induced SAN and PV rates. In the LA, levosimendan at 0.3 and 1 μM shortened the AP duration, and increased contractility at 0.03, 0.1, 0.3, and 1 μM. In contrast, levosimendan did not change the RA contractility, and shortened the AP duration only at 1 μM. Levosimendan increased PV arrhythmogenesis through activating endothelial PDE III and the KATP , and modulating PV tension.

Hydrogen sulphide increases pulmonary veins and atrial arrhythmogenesis with activation of protein kinase C.

Hydrogen sulphide (H2S), one of the most common toxic air pollutants, is an important aetiology of atrial fibrillation (AF). Pulmonary veins (PVs) and left atrium (LA) are the most important AF trigger and substrate. We investigated whether H2S may modulate the arrhythmogenesis of PVs and atria. Conventional microelectrodes and whole‐cell patch clamp were performed in rabbit PV, sinoatrial node (SAN) or atrial cardiomyocytes before and after the perfusion of NaHS with or without chelerythrine (a selective PKC inhibitor), rottlerin (a specific PKC δ inhibitor) or KB‐R7943 (a NCX inhibitor). NaHS reduced spontaneous beating rates, but increased the occurrences of delayed afterdepolarizations and burst firing in PVs and SANs. NaHS (100 μmol/L) increased IKATP and INCX in PV and LA cardiomyocytes, which were attenuated by chelerythrine (3 μmol/L). Chelerythrine, rottlerin (10 μmol/L) or KB‐R7943 (10 μmol/L) attenuated the arrhythmogenic effects of NaHS on PVs or SANs. NaHS shortened the action potential duration in LA, but not in right atrium or in the presence of chelerythrine. NaHS increased PKC activity, but did not translocate PKC isoforms α, ε to membrane in LA. In conclusion, through protein kinase C signalling, H2S increases PV and atrial arrhythmogenesis, which may contribute to air pollution‐induced AF.

Associations of Obstructive Sleep Apnea With Atrial Fibrillation and Continuous Positive Airway Pressure Treatment

Obstructive sleep apnea (OSA) is the most common clinically significant breathing abnormality during sleep. It is highly prevalent among patients with atrial fibrillation (AF), and it promotes arrhythmogenesis and impairs treatment efficacy. The prevalence of OSA ranges from 3% to 49% in population-based studies and from 21% to 74% in patients with AF. Diagnosis and treatment of OSA in patients with AF requires a close interdisciplinary collaboration between electrophysiologists, cardiologists, and sleep specialists. Because the prevalence of OSA is high in patients with AF and most do not report daytime sleepiness, sleep-study evaluation may be reasonable for patients being considered for rhythm control strategy. Acute, transient apnea-associated atrial electrophysiological changes and increased occurrence of AF triggers associated with short episodes of intermittent deoxygenation and reoxygenation, intrathoracic pressure changes during obstructed breathing efforts, and sympathovagal activation combine to create a stimulus for AF triggers and a complex and dynamic substrate for AF during sleep. Repeated episodes of long-term OSA are eventually associated with structural remodeling and changes in electrical conduction in the atrium. Observational data suggest OSA reduces the efficacy of catheter-based and pharmacological antiarrhythmic therapy. Nonrandomized studies have shown that treatment of OSA by continuous positive airway pressure can help to maintain a sinus rhythm after electrical cardioversion and catheter ablation in patients with AF. However, it remains unclear which sleep apnea metric should be used to determine severity and guide such treatment in patients with AF. Data from nonrandomized studies of patients with AF suggest that treatment of OSA by continuous positive airway pressure may help to maintain sinus rhythm after electrical cardioversion and improve catheter ablation success rates. Randomized clinical trials are needed to confirm the association between OSA and AF the benefits of treatment of OSA and the need for and cost-effectiveness of routine OSA screening and treatment.

Doxycycline attenuates chronic intermittent hypoxia-induced atrial fibrosis in rats.

Atrial structural remodeling in the form of fibrosis contributes to the arrhythmic substrate in atrial fibrillation (AF). The aim of this study was to investigate the effects of doxycycline on chronic intermittent hypoxia (CIH)-induced atrial fibrosis and the pathophysiological mechanisms underlying such changes. A total of 30 Sprague Dawley rats were randomized into three groups: control group, CIH group, and CIH with doxycycline treatment (CIH-D) group. CIH lasted 5hours per day for 4weeks. CIH-D rats were administrated doxycycline for 4weeks, while they received CIH. Masson's trichrome staining was used to determine collagen deposit in the atrial myocardium. Protein and mRNA levels of Matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9), microRNA-21 (miR-21) and its downstream target Sprouty1 (Spry1), and extracellular signal-regulated kinases 1/2 (ERK1/2) were measured using Western blotting or real-time qRT-PCR, respectively. Compared to the control group, the CIH group showed higher interstitial collagen fraction, increased MMP-9, miR-21, and p-ERK1/2 levels, and decreased MMP-2 and Spry1 levels. Doxycycline treatment attenuated CIH-induced atrial fibrosis, reduced MMP-2, MMP-9, miR-21, and p-ERK1/2, and increased Spry1. CIH treatment induced significant atrial fibrosis in our rat model, which was attenuated by doxycycline. These changes can be explained by alterations in the MMP and miR-21/ERK signaling pathways.

P1145Different electroanatomic substrates plays different role as the substrate of atrial fibrillation in human

P1145Different electroanatomic substrates plays different role as the substrate of atrial fibrillation in human

EFFECTS OF OBSTRUCTIVE SLEEP APNEA ON THE OUTCOMES OF ATRIAL FIBRILLATION: A NATIONWIDE ANALYSIS

Studies suggest patients with atrial fibrillation (AF) who also suffer from obstructive sleep apnea (OSA) might have a different response to ablative procedures. It has been hypothesized that AF substrates and pathophysiology in these patients might be different from patients with primary AF. Data

203Association between different cardiac MRI parameters with electro-anatomical substrate and NT-proANP levels in atrial fibrillation

203Association between different cardiac MRI parameters with electro-anatomical substrate and NT-proANP levels in atrial fibrillation

P797Effect of sodium channel blockade on the 3-dimensional substrate of atrial fibrillation: a simulation study

P797Effect of sodium channel blockade on the 3-dimensional substrate of atrial fibrillation: a simulation study

Shengmai San-derived herbal prevents the development of a vulnerable substrate for atrial fibrillation in a rat model of ischemic heart failure

ObjectiveThe study aimed to investigate whether a Shengmai San-derived herbal, Fumai granule (FM), which had a preventive effect on atrial fibrillation (AF) in myocardial infarction (MI)-induced heart failure (HF) rat and to determine the underlying mechanisms. Design and methodsMI was induced by a ligation of the left anterior descending coronary artery. One week after MI surgery, FM was gavaged for 4 weeks. AF inducibility was detected by transesophageal programmed electrical stimulation technology. Multielectrode array measurements, echocardiogram, histology, and western blotting were performed. ResultsThe FM-treated group had lower rates of AF inducibility and shorter AF duration compared to the MI group. FM improved the conduction velocity and homogeneity, decreased left atrial positive fibrosis areas and expression of type I and III collagen, inhibited cardiac fibroblast to myofibroblast differential, and increased the expression of connexin 43 and connexin 40 in the left atrium. ConclusionsThese results suggest that FM reduced the AF inducibility after MI by improving the left atrial conduction function via inhibiting left atrial fibrosis and increasing the expression of connexin, indicating its benefit in preventing the MI-induced vulnerable substrate for AF.

Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria

Whereas molecular mechanisms of atrial fibrillation (AF) have been widely investigated, there is limited information regarding interrelation between chronic volume overload and parasympathetic nervous system in the pathophysiology of AF. In this study, we investigated the influence of abdominal aorto-venocaval shunt (AVS)-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. Interstitial fibrosis, cardiomyocyte hypertrophy and atrial enlargement, known as structural arrhythmogenic substrates for AF, took place after one month of AVS operation. Carbachol at 0.1 and 1 μM shortened the effective refractory period, acting as functional arrhythmogenic substrates, but increased the conduction velocity both in the atria of the sham-operated and AVS rats. The extents of the electrophysiological responses to carbachol in the atria of the AVS rat were greater than those in the sham-operated ones. Also, the higher inducibility and longer duration of carbachol-mediated AF were detected in the AVS atria than those in the sham-operated ones. These results showed that chronic volume overload-induced atrial remodeling promoted electrophysiological responses to cholinergic receptor stimulation in the isolated atria of rats, suggesting possible synergistic actions between structural arrhythmogenic substrate in the remodeled atria and functional arrhythmogenic substrates modulated by parasympathetic nerve activity.

High-Density Mapping of the Substrate for Atrial Fibrillation in Obstructive Sleep Apnoea: Relationship with Atrial Fibrillation Phenotype

Background: Obstructive sleep apnoea (OSA) has been associated with atrial fibrillation (AF) and may have important implications for the atrial substrate. The AF substrate in OSA has not been evaluated in relation to the AF phenotype.

High-Density Mapping of the Substrate for Atrial Fibrillation in Obstructive Sleep Apnoea: Implications for the Crista Terminalis and Posterior Right Atrium

High-Density Mapping of the Substrate for Atrial Fibrillation in Obstructive Sleep Apnoea: Implications for the Crista Terminalis and Posterior Right Atrium

Combined Analysis of Human and Experimental Murine Samples Identified Novel Circulating MicroRNAs as Biomarkers for Atrial Fibrillation.

Recent experimental studies have demonstrated that several microRNAs (miRNAs) expressed in atrial tissue promote a substrate of atrial fibrillation (AF). However, because it has not been fully elucidated whether these experimental data contribute to identifying circulating miRNAs as biomarkers for AF, we used a combined analysis of human serum and murine atrial samples with the aim of identifying these biomarkers for predicting AF.Methods and Results:Comprehensive analyses were performed to screen 733 miRNAs in serum from 10 AF patients and 5 controls, and 672 miRNAs in atrial tissue from 6 inducible atrial tachycardia model mice and 3 controls. We selected miRNAs for which expression was detected in both analyses, and their expression levels were changed in the human analyses, the murine analyses, or both. This screening identified 11 candidate miRNAs. Next, we quantified the selected miRNAs using a quantitative RT-PCR in 50 AF and 50 non-AF subjects. The individual assessment revealed that 4 miRNAs (miR-99a-5p, miR-192-5p, miR-214-3p, and miR-342-5p) were significantly upregulated in AF patients. A receiver-operating characteristics curve indicated that miR-214-3p and miR-342-5p had the highest accuracy. The combination of the 4 miRNAs modestly improved the predictive accuracy for AF (76% sensitivity, 80% specificity). Novel circulating miRNAs were upregulated in the serum of AF patients and might be potential biomarkers of AF.

Multimodal Examination of Atrial Fibrillation Substrate: Correlation of Left Atrial Bipolar Voltage Using Multi-Electrode Fast Automated Mapping, Point-by-Point Mapping, and Magnetic Resonance Image Intensity Ratio.

Bipolar voltage mapping, as part of atrial fibrillation (AF) ablation, is traditionally performed in a point-by-point (PBP) approach using single-tip ablation catheters. Alternative techniques for fibrosis-delineation include fast-anatomical mapping (FAM) with multi-electrode circular catheters, and late gadolinium-enhanced magnetic-resonance imaging (LGE-MRI). The correlation between PBP, FAM, and LGE-MRI fibrosis assessment is unknown. In this study, we examined AF substrate using different modalities (PBP, FAM, and LGE-MRI mapping) in patients presenting for an AF ablation. LGE-MRI was performed pre-ablation in 26 patients (73% males, age 63±8years). Local image-intensity ratio (IIR) was used to normalize myocardial intensities. PBP- and FAM-voltage maps were acquired, in sinus rhythm, prior to ablation and co-registered to LGE-MRI. Mean bipolar voltage for all 19,087 FAM voltage points was 0.88±1.27mV and average IIR was 1.08±0.18. In an adjusted mixed-effects model, each unit increase in local IIR was associated with 57% decrease in bipolar voltage (p<0.0001). IIR of >0.74 corresponded to bipolar voltage <0.5 mV. A total of 1554 PBP-mapping points were matched to the nearest FAM-point. In an adjusted mixed-effects model, log-FAM bipolar voltage was significantly associated with log-PBP bipolar voltage (ß=0.36, p<0.0001). At low-voltages, FAM-mapping distribution was shifted to the left compared to PBP-mapping; at intermediate voltages, FAM and PBP voltages were overlapping; and at high voltages, FAM exceeded PBP-voltages. LGE-MRI, FAM and PBP-mapping show good correlation in delineating electro-anatomical AF substrate. Each approach has fundamental technical characteristics, the awareness of which allows proper assessment of atrial fibrosis.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Abstract 20912: The Impact of Mitral Valve Disease on Atrial Fibrillation Ablation Outcome

Introduction: Mitral Valve Disease (MVD) is associated with atrial fibrillation (AF) and can worsen its prognosis. Left Atrial (LA) fibrosis is a known substrate for AF and its extent affects the management. Hypothesis: We hypothesize MVD increases LA fibrosis in AF patients and the chance of AF ablation failure. Secondly, even in patients with low levels of LA fibrosis that are optimal candidates for ablation, presence of MVD still worsens the outcome. Methods: Patients were categorized in two groups: 140 patients had coexisting MVD and AF, and 100 patients AF without MVD. MVD was defined as any dysfunctionality of mitral valve including mitral stenosis, mitral regurgitation, and history of previous mitral valve surgery . LA fibrosis was quantified by Late Gadolinium Enhancement MRI (LGE-MRI). Baseline characteristics were gathered through chart reviewing. Following ablation, patients were followed for median of 71 months for AF recurrence. Results: Patients were 76.4 ± 10.7 years of age in MVD+AF group and 64.2 ± 14.7 in AF group (p &lt; 0.0001). Extent of LA fibrosis was 18.1% ± 9.3 and 10.3% ± 5.3 in MVD+AF and AF group, respectively (p &lt; 0.0001). The result of our statistical model adjusted for possible cofounders showed that coexistence of MVD in AF patients result in presence of 6.4% more LA fibrosis (p &lt; 0.00001) and lowered the chance of remaining AF free after the ablation (recurrence-free ratio of 0.554 vs 0.757 in MVD+AF and AF group respectively, P &lt; 0.05) (Figure 1). In patients with LA fibrosis less than 20% who would be ideal AF ablation candidate, the presence of MVD decreased the chance to remain AF free (0.574 vs 0.775 in MVD+AF and AF respectively, p &lt; 0.05) (Figure 2). Conclusions: MVD increases LA fibrosis in AF patients and the chance of AF recurrence post-ablation.

Abstract 21007: Role of Thick Fibrotic Tissue in the Left Atrium on the Outcome of Atrial Fibrillation Ablation

Introduction: Left Atrial (LA) Fibrosis may serve as a substrate for Atrial Fibrillation (AF) and the total percentage of LA fibrosis affects the outcome of ablation therapy. But the role of “thick” (transmural or near transmural) fibrotic tissue, as opposed to superficial fibrosis, in the AF prognosis is not well studied. We assess the amount of LA wall fibrosis thickness on AF ablation outcome. Methods and Results: Patients’ parameters were obtained from DECAAF trial. LA fibrosis was quantified with Late Gadolinium Enhancement MRI (LGE-MRI) and when within LA myocardium, 3 or more voxels (each voxel = 0.625mm) were enhanced that area was considered as thick fibrotic tissue. First Cox regression was devised to measure the impact of thick fibrosis on the outcome of AF ablation. Then patients were divided into 2 groups: First group with more than 3.89% of thick LA fibrosis and the second group with less than that. This cut-off was achieved through Receiver Operation Curve analysis of our cohort. Patients were 58.9 ± 10.9 of age and their amount of thick LA fibrosis was 3.5% ± 2.4%. The result of Cox regression showed: 1% increase in the extent of thick LA fibrosis, the recurrence rate of AF increases by 20% after ablation. (HR = 1.2, CI 95% = 1.1 - 1.3, P &lt; 0.0001). The first and second group matched in terms of age, gender, LA volume, and co-morbidities. The first group were 2.9 times more at risk for AF recurrence after the ablation (CI95% = 1.9 - 4.5, P &lt; 0.001) and they had a significantly lower chance of remaining AF free after ablation (0.385 vs 0.621, P &lt; 0.0001) Conclusions: We found the percentage of LA wall fibrosis thickness to correlate with a worse AF ablation outcome and an increased risk of AF recurrence. Therefore assessing percentage of thick fibrotic tissue within LA wall may be of a greater interest than assessing total percentage of fibrosis.