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1.
A survey of pathways for mechano-electric coupling in the atria.
Marta Varela, , Roy, A, Lee, J
Progress in biophysics and molecular biology. 2021;:136-145
Abstract
Mechano-electric coupling (MEC) in atrial tissue has received sparse investigation to date, despite the well-known association between chronic atrial dilation and atrial fibrillation (AF). Of note, no fewer than six different mechanisms pertaining to stretch-activated channels, cellular capacitance and geometric effects have been identified in the literature as potential players. In this mini review, we briefly survey each of these pathways to MEC. We then perform computational simulations using single cell and tissue models in presence of various stretch regimes and MEC pathways. This allows us to assess the relative significance of each pathway in determining action potential duration, conduction velocity and rotor stability. For chronic atrial stretch, we find that stretch-induced alterations in membrane capacitance decrease conduction velocity and increase action potential duration, in agreement with experimental findings. In the presence of time-dependent passive atrial stretch, stretch-activated channels play the largest role, leading to after-depolarizations and rotor hypermeandering. These findings suggest that physiological atrial stretches, such as passive stretch during the atrial reservoir phase, may play an important part in the mechanisms of atrial arrhythmogenesis.
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Alpha and beta myosin isoforms and human atrial and ventricular contraction.
Walklate, J, Ferrantini, C, Johnson, CA, Tesi, C, Poggesi, C, Geeves, MA
Cellular and molecular life sciences : CMLS. 2021;(23):7309-7337
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Human atrial and ventricular contractions have distinct mechanical characteristics including speed of contraction, volume of blood delivered and the range of pressure generated. Notably, the ventricle expresses predominantly β-cardiac myosin while the atrium expresses mostly the α-isoform. In recent years exploration of the properties of pure α- & β-myosin isoforms have been possible in solution, in isolated myocytes and myofibrils. This allows us to consider the extent to which the atrial vs ventricular mechanical characteristics are defined by the myosin isoform expressed, and how the isoform properties are matched to their physiological roles. To do this we Outline the essential feature of atrial and ventricular contraction; Explore the molecular structural and functional characteristics of the two myosin isoforms; Describe the contractile behaviour of myocytes and myofibrils expressing a single myosin isoform; Finally we outline the outstanding problems in defining the differences between the atria and ventricles. This allowed us consider what features of contraction can and cannot be ascribed to the myosin isoforms present in the atria and ventricles.
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Afterdepolarizations and abnormal calcium handling in atrial myocytes with modulated SERCA uptake: a sensitivity analysis of calcium handling channels.
Lo, ACY, Bai, J, Gladding, PA, Fedorov, VV, Zhao, J
Philosophical transactions. Series A, Mathematical, physical, and engineering sciences. 2020;(2173):20190557
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Abstract
Delayed afterdepolarizations (DADs) and spontaneous depolarizations (SDs) are typically triggered by spontaneous diastolic Ca2+ release from the sarcoplasmic reticulum (SR) which is caused by an elevated SR Ca2+-ATPase (SERCA) uptake and dysfunctional ryanodine receptors. However, recent studies on the T-box transcription factor gene (TBX5) demonstrated that abnormal depolarizations could occur despite a reduced SERCA uptake. Similar findings have also been reported in experimental or clinical studies of diabetes and heart failure. To investigate the sensitivity of SERCA in the genesis of DADs/SDs as well as its dependence on other Ca2+ handling channels, we performed systematic analyses using the Maleckar et al. model. Results showed that the modulation of SERCA alone cannot trigger abnormal depolarizations, but can instead affect the interdependency of other Ca2+ handling channels in triggering DADs/SDs. Furthermore, we discovered the existence of a threshold value for the intracellular concentration of Ca2+ ([Ca2+]i) for abnormal depolarizations, which is modulated by the maximum SERCA uptake and the concentration of Ca2+ in the uptake and release compartments in the SR ([Ca2+]up and [Ca2+]rel). For the first time, our modelling study reconciles different mechanisms of abnormal depolarizations in the setting of 'lone' AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
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Remodeling Promotes Proarrhythmic Disruption of Calcium Homeostasis in Failing Atrial Myocytes.
Shiferaw, Y, Aistrup, GL, Louch, WE, Wasserstrom, JA
Biophysical journal. 2020;(2):476-491
Abstract
It is well known that heart failure (HF) typically coexists with atrial fibrillation (AF). However, until now, no clear mechanism has been established that relates HF to AF. In this study, we apply a multiscale computational framework to establish a mechanistic link between atrial myocyte structural remodeling in HF and AF. Using a spatially distributed model of calcium (Ca) signaling, we show that disruption of the spatial relationship between L-type Ca channels (LCCs) and ryanodine receptors results in markedly increased Ca content of the sarcoplasmic reticulum (SR). This increase in SR load is due to changes in the balance between Ca entry via LCCs and Ca extrusion due to the sodium-calcium exchanger after an altered spatial relationship between these signaling proteins. Next, we show that the increased SR load in atrial myocytes predisposes these cells to subcellular Ca waves that occur during the action potential (AP) and are triggered by LCC openings. These waves are common in atrial cells because of the absence of a well-developed t-tubule system in most of these cells. This distinct spatial architecture allows for the presence of a large pool of orphaned ryanodine receptors, which can fire and sustain Ca waves during the AP. Finally, we incorporate our atrial cell model in two-dimensional tissue simulations and demonstrate that triggered wave generation in cells leads to electrical waves in tissue that tend to fractionate to form wavelets of excitation. This fractionation is driven by the underlying stochasticity of subcellular Ca waves, which perturbs AP repolarization and consequently induces localized conduction block in tissue. We outline the mechanism for this effect and argue that it may explain the propensity for atrial arrhythmias in HF.
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Correlation between left atrial spontaneous echocardiographic contrast and 5-year stroke/death in patients with non-valvular atrial fibrillation.
Soulat-Dufour, L, Lang, S, Etienney, A, Ederhy, S, Ancedy, Y, Adavane, S, Chauvet-Droit, M, Nhan, P, Di Angelantonio, E, Boccara, F, et al
Archives of cardiovascular diseases. 2020;(8-9):525-533
Abstract
BACKGROUND Transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) can be used to detect the presence of left atrial thrombus and left atrial spontaneous echocardiographic contrast (LASEC). AIM: To evaluate the prognostic value of TTE and TOE in predicting stroke and all-cause death at 5-year follow-up in patients with non-valvular atrial fibrillation (NVAF). METHODS This study included patients hospitalised with electrocardiography-diagnosed NVAF in Saint-Antoine University Hospital, Paris, between July 1998 and December 2011, who underwent TTE and TOE evaluation within 24hours of admission. Cox proportional-hazards models were used to identify predictors of the composite outcome (stroke or all-cause death). RESULTS During 5 years of follow-up, stroke/death occurred in 185/903 patients (20.5%). By multivariable analysis, independent predictors of stroke/death were CHA2DS2-VASc score (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.25-1.47; P<0.001), left atrial area>20 cm2 (HR 1.59, 95% CI 1.08-2.35; P=0.018), moderate LASEC (HR 1.72, 95% CI 1.13-2.62; P=0.012) and severe LASEC (HR 2.04, 95% CI 1.16-3.58; P=0.013). Independent protective predictors were dyslipidaemia (HR 0.60, 95% CI 0.43-0.83; P=0.002) and discharge prescription of anti-arrhythmics (HR 0.59, 95% CI 0.40-0.87; P=0.008). Adding LASEC to the CHA2DS2-VASc score modestly improved predictive accuracy and risk classification, with a C index of 0.71 vs. 0.69 (P=0.004). CONCLUSIONS In this retrospective monocentric study, the presence of moderate/severe LASEC was an independent predictor of stroke/death at 5-year follow-up in patients with NVAF. The inclusion of LASEC in stroke risk scores could modestly improve risk stratification.
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Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation.
Hall, AW, Chaffin, M, Roselli, C, Lin, H, Lubitz, SA, Bianchi, V, Geeven, G, Bedi, K, Margulies, KB, de Laat, W, et al
Circulation. Genomic and precision medicine. 2020;(6):e003085
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Abstract
BACKGROUND Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes. METHODS We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (P<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes. RESULTS Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (P<2×10-16). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (P<2×10-16). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5, TBX3, ZFHX3, and SYNPO2L. CONCLUSIONS Profiling the noncoding genome provides new insights into the gene expression and chromatin regulation in human LA tissue. These findings enabled identification of a gene network underlying AF; our experimental and analytic approach can be extended to identify molecular mechanisms for other cardiac diseases and traits.
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The role of long noncoding RNAs in atrial fibrillation.
Babapoor-Farrokhran, S, Gill, D, Rasekhi, RT
Heart rhythm. 2020;(6):1043-1049
Abstract
Atrial fibrillation (AF) is a common arrhythmia with serious clinical sequelae, yet little is known about its genetic origins. Recently, the untranscribed 98% of the human genome has been increasingly implicated in important processes such as cardiac organogenesis, physiology, and pathophysiology. Specifically, long noncoding RNAs (lncRNAs) have been shown to interact with the transcriptome in various ways that alter gene expression. Previously, multiple lncRNAs have been identified in disease processes such as heart failure, coronary artery disease, and diabetes. Multiple studies now show lncRNAs are involved in each fundamental mechanism leading to the development of AF, including structural remodeling, electrical remodeling, renin angiotensin system effects, and calcium handling abnormalities. The altered expression of lncRNAs offers genetic targets for the diagnosis and treatment of AF. This article discusses the role of lncRNAs in AF and its pathogenesis.
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Atrial high-rate episodes: prevalence, stroke risk, implications for management, and clinical gaps in evidence.
Bertaglia, E, Blank, B, Blomström-Lundqvist, C, Brandes, A, Cabanelas, N, Dan, GA, Dichtl, W, Goette, A, de Groot, JR, Lubinski, A, et al
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2019;(10):1459-1467
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Abstract
Self-terminating atrial arrhythmias are commonly detected on continuous rhythm monitoring, e.g. by pacemakers or defibrillators. It is unclear whether the presence of these arrhythmias has therapeutic consequences. We sought to summarize evidence on the prevalence of atrial high-rate episodes (AHREs) and their impact on risk of stroke. We performed a comprehensive, tabulated review of published literature on the prevalence of AHRE. In patients with AHRE, but without atrial fibrillation (AF), we reviewed the stroke risk and the potential risk/benefit of oral anticoagulation. Atrial high-rate episodes are found in 10-30% of AF-free patients. Presence of AHRE slightly increases stroke risk (0.8% to 1%/year) compared with patients without AHRE. Atrial high-rate episode of longer duration (e.g. those >24 h) could be associated with a higher stroke risk. Oral anticoagulation has the potential to reduce stroke risk in patients with AHRE but is associated with a rate of major bleeding of 2%/year. Oral anticoagulation is not effective in patients with heart failure or survivors of a stroke without AF. It remains unclear whether anticoagulation is effective and safe in patients with AHRE. Atrial high-rate episodes are common and confer a slight increase in stroke risk. There is true equipoise on the best way to reduce stroke risk in patients with AHRE. Two ongoing trials (NOAH-AFNET 6 and ARTESiA) will provide much-needed information on the effectiveness and safety of oral anticoagulation using non-vitamin K antagonist oral anticoagulants in patients with AHRE.
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Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium.
Ni, H, Zhang, H, Grandi, E, Narayan, SM, Giles, WR
American journal of physiology. Heart and circulatory physiology. 2019;(3):H527-H542
Abstract
Efforts to identify the mechanisms for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in specific elements of the atrial "substrate," i.e., its electrophysiological properties and/or structural components. We used experimentally validated mathematical models of the human atrial myocyte action potential (AP), both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current ( Ito) to electrophysiological instability and arrhythmia initiation. First, we explored whether changes in the recovery or restitution of the AP duration (APD) and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified disease-dependent spatial differences in expression levels of the specific K+ channel α-subunits that underlie Ito in the left atrium. Therefore, we studied the functional consequences of this by deletion of 50% of native Ito (Kv4.3) and its replacement with Kv1.4. Interestingly, significant changes in the short-term stability of the human atrial AP waveform were revealed. Specifically, this K+ channel isoform switch produced discontinuities in the initial slope of the APD restitution curve and appearance of APD alternans. This pattern of in silico results resembles some of the changes observed in high-resolution clinical electrophysiological recordings. Important insights into mechanisms for these changes emerged from known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. These results suggest new approaches for pharmacological management of AF, based on molecular properties of specific K+ isoforms and their changed expression during progressive disease. NEW & NOTEWORTHY Clinical studies identify oscillations (alternans) in action potential (AP) duration as a predictor for atrial fibrillation (AF). The abbreviated AP in AF also involves changes in K+ currents and early repolarization of the AP. Our simulations illustrate how substitution of Kv1.4 for the native current, Kv4.3, alters the AP waveform and enhances alternans. Knowledge of this "isoform switch" and related dynamics in the AF substrate may guide new approaches for detection and management of AF.
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Comparison of transesophageal echocardiography findings after different anticoagulation strategies in patients with atrial fibrillation: a systematic review and meta-analysis.
Yang, J, Zhang, X, Wang, XY, Zhang, C, Chen, SZ, Hu, SJ
BMC cardiovascular disorders. 2019;(1):261
Abstract
BACKGROUND High risk of embolic events exists in both patients with chronic atrial fibrillation (AF) and patients in the perioperative period of ablation (effective treatment for AF). Therefore, anticoagulant therapy is important. Oral anticoagulants can be divided into two major categories: vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs). VKAs, represented by warfarin, have been widely used as traditional anticoagulants, whereas NOACs have been used in clinical practice, but their anticoagulant effects and side effects are still the focus of research. We used a meta-analysis to compare the incidence of left atrial thrombi (LAT) between different anticoagulants. METHODS We searched PubMed, EMBASE, Web of Science, and the Cochrane Library databases for observational studies that compared the transesophageal echocardiography (TEE) findings for patients treated with NOACs and VKAs. The incidence of LAT and dense spontaneous echocardiographic contrast (dense SEC) were extracted as the basis of the meta-analysis. RESULTS Fifteen studies were included in the meta-analysis. We found that patients anticoagulated with NOACs and VKAs had similar incidence of LAT (OR = 0.74, 95%CI: 0.55-1.00). After excluding the heterogeneous article by sensitivity analysis, we found the incidence of LAT in patients anticoagulated with NOACs is lower than VKAs (OR = 0.59, 95%CI: 0.42-0.84). The results of subgroup analysis showed that the incidence of LAT among three types of NOACs have no significant difference (dabigatran vs. rivaroxaban, OR = 1.16 [0.75, 1.81]; rivaroxaban vs. apixaban, OR = 0.97 [0.54, 1.74]; dabigatran vs. apixaban, OR = 1.09 [0.55, 2.16]). CONCLUSION Patients anticoagulated with NOACs may have lower incidence of LAT than VKAs. The incidence of LAT among different type of NOACs are similar.