Substrate For Atrial Fibrillation Research Articles

In silico Comparison of Left Atrial Ablation Techniques That Target the Anatomical, Structural, and Electrical Substrates of Atrial Fibrillation.

Catheter ablation therapy for persistent atrial fibrillation (AF) typically includes pulmonary vein isolation (PVI) and may include additional ablation lesions that target patient-specific anatomical, electrical, or structural features. Clinical centers employ different ablation strategies, which use imaging data together with electroanatomic mapping data, depending on data availability. The aim of this study was to compare ablation techniques across a virtual cohort of AF patients. We constructed 20 paroxysmal and 30 persistent AF patient-specific left atrial (LA) bilayer models incorporating fibrotic remodeling from late-gadolinium enhancement (LGE) MRI scans. AF was simulated and post-processed using phase mapping to determine electrical driver locations over 15 s. Six different ablation approaches were tested: (i) PVI alone, modeled as wide-area encirclement of the pulmonary veins; PVI together with: (ii) roof and inferior lines to model posterior wall box isolation; (iii) isolating the largest fibrotic area (identified by LGE-MRI); (iv) isolating all fibrotic areas; (v) isolating the largest driver hotspot region [identified as high simulated phase singularity (PS) density]; and (vi) isolating all driver hotspot regions. Ablation efficacy was assessed to predict optimal ablation therapies for individual patients. We subsequently trained a random forest classifier to predict ablation response using (a) imaging metrics alone, (b) imaging and electrical metrics, or (c) imaging, electrical, and ablation lesion metrics. The optimal ablation approach resulting in termination, or if not possible atrial tachycardia (AT), varied among the virtual patient cohort: (i) 20% PVI alone, (ii) 6% box ablation, (iii) 2% largest fibrosis area, (iv) 4% all fibrosis areas, (v) 2% largest driver hotspot, and (vi) 46% all driver hotspots. Around 20% of cases remained in AF for all ablation strategies. The addition of patient-specific and ablation pattern specific lesion metrics to the trained random forest classifier improved predictive capability from an accuracy of 0.73 to 0.83. The trained classifier results demonstrate that the surface areas of pre-ablation driver regions and of fibrotic tissue not isolated by the proposed ablation strategy are both important for predicting ablation outcome. Overall, our study demonstrates the need to select the optimal ablation strategy for each patient. It suggests that both patient-specific fibrosis properties and driver locations are important for planning ablation approaches, and the distribution of lesions is important for predicting an acute response.

Obesity and Atrial Fibrillation: Should We Screen for Atrial Fibrillation in Obese Individuals? A Comprehensive Review.

Obesity and obesity-related illnesses (ORIs) constitute a significant burden on the healthcare system, with a very high prevalence in the general population. Atrial fibrillation (AF) is the most common arrhythmia seen by healthcare providers. The risk of AF in obese individuals is reported to be high and in correlation with Body Mass Index (BMI), leading to the high prevalence of AF in the general population and the expected epidemic of AF to come. Greater left atrial dimensions and left atrial remodeling together form the AF substrate in the obese population along with the role of epicardial adipose tissue (EAT) in inducing inflammation and fibrosis of the atrial myocardium and thus facilitating the onset of AF. In our paper, we reviewed the literature published on the link between obesity and AF, as well as the potential behind new management approaches. Multiple studies have explored different approaches, either conventional or novel. Considering the impact of prevention in medicine nowadays, we proposed a screening practice for AF in obese individuals. More research is needed to acquire a comprehensive protocol for the management of AF in the obese population that can be applied by primary healthcare providers to combat this evolving matter.

Epicardial Adipose Tissue Accumulation Confers Atrial Conduction Abnormality

BackgroundClinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined. ObjectivesThe purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF. MethodsPatients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance. ResultsHigher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity. ConclusionsThese findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate.

Toward Mechanism-Directed Electrophenotype-Based Treatments for Atrial Fibrillation.

Current treatment approaches for persistent atrial fibrillation (AF) have a ceiling of success of around 50%. This is despite 15 years of developing adjunctive ablation strategies in addition to pulmonary vein isolation to target the underlying arrhythmogenic substrate in AF. A major shortcoming of our current approach to AF treatment is its predominantly empirical nature. This has in part been due to a lack of consensus on the mechanisms that sustain human AF. In this article, we review evidence suggesting that the previous debates on AF being either an organized arrhythmia with a focal driver or a disorganized rhythm sustained by multiple wavelets, may prove to be a false dichotomy. Instead, a range of fibrillation electrophenotypes exists along a continuous spectrum, and the predominant mechanism in an individual case is determined by the nature and extent of remodeling of the underlying substrate. We propose moving beyond the current empirical approach to AF treatment, highlight the need to prescribe AF treatments based on the underlying AF electrophenotype, and review several possible novel mapping algorithms that may be useful in discerning the AF electrophenotype to guide tailored treatments, including Granger Causality mapping.

Right Atrial Complexity Evolves With Stepwise Left-Sided Persistent Atrial Fibrillation Substrate Ablation and Predicts Outcomes.

This study sought to study the relation between outcomes of modified stepwise atrial fibrillation (AF) substrate ablation and dynamic electrogram characteristics in the coronary sinus (CS) and right atrium (RA). Identifying patients with persistent AF who will benefit from limited lesion sets versus those requiring extensive substrate modification is challenging. We studied 70 patients undergoing persistent AF ablation, 43 with acute success (successful ablation [sABL], AF termination, or noninducibility) and 27 with failure (failed ablation [fABL], no termination, or induced AF of >5minutes). Dominant frequency (DF) and sample entropy (SampEn, increasing with signal complexity) were measured on 30-second recordings of wide-coverage simultaneous RA and CS electrograms during baseline AF and induced AF post-pulmonary vein isolation and after left-sided electrogram-guided ablation steps (on the CS with or without the left atrium [LA]). At baseline AF, patients with sABL exhibited lower RA SampEn (p=0.023) and lower CS DF (p=0.030) compared to fABL. A positive RA-to-CS SampEn gradient predicted ablation failure (48% vs. 19% for patients in fABL vs. sABL; p=0.015). A positive RA-to-CS DF gradient developed in patients with fABL after extra-pulmonary vein substrate modification, unlike patients with sABL (p=0.0008). At 24months, 76% of patients were AF free, and 68% were arrhythmia free. sABL was associated with fewer AF recurrences (hazard ratio: 0.31; 95% confidence interval: 0.12-0.84; p=0.021). A negative RA-to-CS SampEn gradient at baseline was associated with freedom from AF (-0.14 ± 0.19 vs. 0.04 ± 0.18; p=0.002). RA greater than CS electrogram complexity gradients at baseline or developing during ablation are associated with unfavorable acute and long-term outcomes of persistent AF ablation. These parameters allow monitoring of the effects of left-sided substrate ablation and, therefore, a rational choice of additional RA substrate modification.

Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation.

Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown. To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery. Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca2+]i-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca2+-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca2+-release events and L-type Ca2+-current alternans occurred more frequently. CaMKII (Ca2+/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca2+-content was unchanged in POAF despite greater SR Ca2+-leak, with a trend towards increased SR Ca2+-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca2+-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca2+-uptake are sufficient to reproduce the Ca2+-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β. Preexisting Ca2+-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca2+-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Efficacy of an Adjunctive Electrophysiological Test-Guided Left Atrial Posterior Wall Isolation in Persistent Atrial Fibrillation Without a Left Atrial Low-Voltage Area.

Electrical remodeling precedes structural remodeling. In adjunctive left atrial (LA) low-voltage area (LVA) ablation to pulmonary vein isolation of atrial fibrillation (AF), LA areas without LVA have not been targeted for ablation. We studied the effect of adjunctive LA posterior wall isolation (PWI) on persistent AF without LA-LVA according to electrophysiological testing (EP test). We examined consecutive patients with persistent AF with (n=33) and without (n=111) LA-LVA. Patients without LA-LVA were randomly assigned to EP test-guided (n=57) and control (n=54) groups. In the EP test-guided group, an adjunctive PWI was performed in those with positive results (PWI subgroup; n=24), but not in those with negative results (n=33). The criteria for positive EP tests were an effective refractory period ≤180 ms, effective refractory period>20 ms shorter than the other sites, and/or induction of AF/atrial tachycardia (AT) during measurements. LVA ablation was performed in the patients with LA-LVA. During the follow-up period (62±33 weeks), the EP test-guided group had significantly lower recurrence rates (19%,11/57 versus 41%, 22/54, P=0.012) and higher Kaplan-Meier AF/AT-free survival curve rates than the control group (P=0.01). No significant differences in the recurrence and AF/AT-free survival curve rates between the PWI (positive EP test) and non-PWI (negative EP test) subgroups were observed. Therefore, PWI for positive EP tests reduced the AF/AT recurrence in the EP test-guided group. A stepwise Cox proportional hazard analyses identified EP test-guided ablation as a factor reducing the recurrence rate. The recurrence rates in the LA-LVA ablation group and EP test-guided group were similar. This pilot study proposed that an EP test-guided adjunctive PWI of persistent AF without LA-LVA potentially reduced AF/AT recurrences. The results suggest that there is an AF substrate in the LA with altered electrophysiological function even when there is no LA-LVA. Graphic Abstract: A graphic abstract is available for this article.

Morphometric characteristics of myocardial sleeves of the pulmonary veins.

The pulmonary veins are covered by a myocardial layer, which is often an electrical substrate for atrial fibrillation. The aim of this study was to study the morphologic characteristics of the myocardial sleeves of pulmonary veins by examining a large group of freshly autopsied human material. The study macroscopically examined a total of 498 pulmonary veins draining the left atrium (120 unpreserved human hearts). In 75.0% of specimens, a classical pulmonary venous pattern was observed. The remainder of specimens either had an additional middle right pulmonary vein (20.0% of cases) or a common left pulmonary vein (5.0% of cases). Among all the veins seen in the classical pulmonary venous drainage type, the left superior pulmonary vein had the longest myocardial sleeves (9.4 ± 4.6 mm; coverage = 60.1 ± 19.4%), followed by the left inferior pulmonary vein (6.6 ± 3.5 mm; coverage = 47.6 ± 18.3%), the right superior pulmonary vein (6.0 ± 2.7 mm; coverage = 50.5 ± 13.9%) and then the right inferior pulmonary vein (5.0 ± 2.8 mm; coverage = 45.6 ± 16.2%; analysis of variance p < .001). In hearts with an additional right pulmonary vein, this vessel had the shortest myocardial sleeves (2.7 ± 1.1 mm; coverage = 36.0 ± 11.6%). In hearts with a common left pulmonary vein, the myocardial sleeves had the longest course for the common vein (13.7 ± 4.4 mm; coverage = 79.7 ± 4.9%). Myocardial sleeves of the pulmonary veins were seen in each examined specimen, however, their length varied significantly. In hearts with a classical venous drainage pattern, the left superior pulmonary vein had the longest sleeves. When present, an additional middle right pulmonary vein had the shortest myocardial sleeves, while the left common pulmonary vein had the longest sleeves.

1-9HYPERTENSION AND ATRIAL VOLTAGES AT ATRIAL APPENDAGES

Background: Hypertension has been linked with alterations of atrial electrophysiology, which related to the substrate of atrial fibrillation. However, atrial voltages at atrial appendages and their relationship with hypertension remain undiscovered. The study aimed to investigate atrial voltages at both right and left atrial appendages (RAA and LAA) and their correlations with hypertension in patients with underlying heart disease. Materials &amp; Methods: Subjects with ischemic and/or valvular heart disease undergoing cardiac surgery at Erasmus Medical Center Rotterdam were included. After the heart was exposed during open chest surgery, high-resolution epicardial mapping of the LAA and the RAA during sinus rhythm was performed before starting cardiopulmonary bypass. Custom-made software was used to measure atrial voltages. A history of hypertension was obtained from the electronic medical record before undergoing surgery. Results: Among 133 patients undergoing cardiac surgery, 88 patients (66%) had hypertension. Atrial voltages at the LAA were higher in hypertensive patients compared to non-hypertensive patients (median = 5.36 vs 3.59 p &lt; 0.05), also a correlation between hypertension and atrial voltages at the LAA was identified (r = 0.247, p &lt; 0.05). On the other hand, atrial voltages at the RAA were comparable between hypertensive and non-hypertensive patients (median = 4.30 vs 3.96, p &gt; 0.05), without any correlation was found between hypertension and atrial voltages at the RAA. Conclusions: Atrial voltages at the LAA are higher compared to the RAA within hypertensive patients. Hypertension is also correlated with higher atrial voltages at the LAA. High atrial voltages at the LAA might be associated with structural changes of the LAA impacted by systemic hypertension.

A novel framework for noninvasive analysis of short-term atrial activity dynamics during persistent atrial fibrillation

ECG-based representation of atrial fibrillation (AF) progression is currently limited. We propose a novel framework for a more sensitive noninvasive characterization of the AF substrate during persistent AF. An atrial activity (AA) recurrence signal is computed from body surface potential map (BSPM) recordings, and a set of characteristic indices is derived from it which captures the short- and long-term recurrent behaviour in the AA patterns. A novel measure of short- and long-term spatial variability of AA propagation is introduced, to provide an interpretation of the above indices, and to test the hypothesis that the variability in the oscillatory content of AA is due mainly to a spatially uncoordinated propagation of the AF waveforms. A simple model of atrial signal dynamics is proposed to confirm this hypothesis, and to investigate a possible influence of the AF substrate on the short-term recurrent behaviour of AA propagation. Results confirm the hypothesis, with the model also revealing the above influence. Once the characteristic indices are normalized to remove this influence, they show to be significantly associated with AF recurrence 4 to 6 weeks after electrical cardioversion. Therefore, the proposed framework improves noninvasive AF substrate characterization in patients with a very similar substrate.Graphical Schematic representation of the proposed framework for the noninvasive characterization of short-term atrial signal dynamics during persistent AF. The proposed framework shows that the faster the AA is propagating, the more stable its propagation paths are in the short-term (larger values of Speed in the bottom right plot should be interpreted as lower speed of propagation of the corresponding AA propagation patters).

Slow whole left atrial conduction velocity after pulmonary vein isolation predicts atrial fibrillation recurrence.

Atrial conduction velocity may represent atrial fibrillation (AF) substrate after pulmonary vein isolation (PVI). To elucidate the association between whole left atrial conduction velocity (LACV) and AF recurrence after PVI. This observational study enrolled 279 patients (147 paroxysmal and 132 persistent AF) who underwent PVI alone as an initial AF ablation procedure. After PVI, the left atrium was mapped with a 20-pole multielectrode in conjunction with the CARTO3 system during 100-ppm right atrial pacing. Left atrial conduction distance and conduction time were calculated from the start to the end of the propagation wave front in the left atrium. LACVs on the anterior and posterior routes were calculated as conduction distance divided by conduction time. Anterior and posterior LACVs were slower in patients with AF recurrence than in those without (anterior, 0.79 [0.71, 0.86] vs 0.96 [0.90, 1.06] m/s, P < .001; posterior, 0.99 [0.89, 1.14] vs 1.10 [1.00, 1.29] m/s, P < .001). AF recurrence was best predicted by anterior LACV with a cut-off value of 0.87 m/s (sensitivity 87%, specificity 81%, and predictive accuracy 84%). Multivariate analysis demonstrated that a slow anterior LACV <0.87 m/s was an independent predictor of AF recurrence with an adjusted hazard ratio of 11.8 (6.36-22.0). Patients with anterior low-voltage areas demonstrated slower anterior LACV than those without low-voltage areas (0.89 [0.71, 1.00] vs 0.94 [0.87, 1.05] m/s, P < .001). A slow anterior LACV was an excellent predictor of AF recurrence after PVI.

P1010Association between left atrial fibrosis detected by cardiac magnetic resonance and endocardial electroanatomic mapping in the evaluation of the electrophysiological substrate in atrial fibrillation

Abstract Background Atrial fibrillation (AF) is related to left atrial fibrosis, but its identification by late magnetic resonance imaging (LGE) with gadolinium (LGE) persists in controversy due to heterogeneous results in its correlation with the electroatomic map (EAM) and the difficulty of perform histological studies in humans. Purpose We try to examine the point-by-point association between high density EAM and LGE-MRI using an automatic and reproducible method. Methods A LGE-MRI was performed in 16 patients prior to ablation. Three different areas were established depending on the intensity of normalized enhancement for each patient according to their blood group with the image intensity ratio (IIR) (healthy &amp;lt;1.20, border area (BZ) ≥1.20 &amp;lt;1.32 and scar ≥1.32). The high density electroanatomic maps of the left atrium (LA) were projected onto the MRI, obtaining an automatic correlation point by point. Results The study obtained significant differences (p &amp;lt; 0.001) between voltage (mV) and CV (mm/ms) among healthy, BZ and scar areas, as well a significant inverse correlation (p &amp;lt; 0.001) between voltage and IIR (R=-0.39). It obtained too a significant correlation between CV and IIR (R=-0.24), but this showed a greater correlation in those patients who have the least dilated LA (p = 0.02). Conclusions LGE-MRI and EAM showed good correlation in delineating potential pathologic substrate in AF, but left atrium dilation could reduce the performance of the CMR in this task. Conduction velocity could be more sensitive than voltage and LGE-MRI to detect incipient substrate in AF. Voltage and conduction velocity values Area /IIR Velocity (mm/ms) Voltage (mV) I / &amp;lt;.20 1.036(0.913-1.158) 1.593(1.489-1.696) 2 / ≥1.20 and &amp;lt;1.32 0.722(0.590-0.850) 0.792 (0.649-0,935) 3 / ≥1.32 0.623(0.473-0,733) 0.444(0.245-0.642) Voltage and conduction velocity values in the three areas of the LGE-RMN. Abstract Figure. Correlation among voltage, VC and LA

Are the atrial natriuretic peptides a missing link predicting low-voltage areas in atrial fibrillation? Introducing the novel biomarker-based atrial fibrillation substrate prediction (ANP) score.

BackgroundIn patients with atrial fibrillation (AF), left atrial (LA) enlargement, and the presence of low‐voltage areas (LVAs) indicate an advanced disease stage. NT‐proANP is a biomarker, which is significantly higher in both phenotypes. Prediction of LVAs before catheter ablation could impact the prognosis and therapeutical management in AF patients.ObjectiveThe aim of this study was to (a) analyze the predictive value of a novel biomarker‐based AF substrate prediction score, and (b) compare it with DR‐FLASH and APPLE scores.MethodsPatients undergoing first AF catheter ablation were included. LA volume (LAV) was analyzed prior to ablation using cardiovascular magnetic resonance imaging (CMR). Blood plasma samples from the femoral vein were collected before AF ablation. NT‐proANP was analyzed using commercially available assays. LVAs were determined using high‐density maps during catheter ablation and defined as <0.5 mV. The novel ANP score (one point for Age ≥ 65 years, NT‐proANP > 17 ng/mL, and Persistent AF) was calculated at baseline.ResultsThe study population included 156 AF patients (64 ± 10 years, 65% males, 61% persistent AF, 28% LVAs). The cut‐off ANP score ≥ 2 demonstrated 77% sensitivity and 70% specificity. On logistic regression (odds ratio [OR] 3.469) and receiver operating characteristic (ROC) analysis (area under the curve [AUC] 0.778, P < .001), the ANP score significantly predicted LVAs presence. There were no differences between novel ANP score – which is a new one ‐ is described in the ; with APPLE (AUC 0.718, P = .378) and DR‐FLASH (AUC 0.766, P = .856) scores.ConclusionsThe novel biomarker‐based ANP score demonstrates good prediction of LVAs.

Attenuation of atrial remodeling by aliskiren via affecting oxidative stress, inflammation and PI3K/Akt signaling pathway.

Atrial fibrillation (AF) is the most common type of arrhythmia. Atrial remodeling is a major factor to the AF substrate. The purpose of the study is to explore whether aliskiren (ALS) has a cardioprotective effect and its potential molecular mechanisms on atrial remodeling. In acute experiments, dogs were randomly assigned to Sham, Paced and Paced+aliskiren (10mgkg-1) (Paced+ALS) groups, with 7 dogs in each group. Rapid atrial pacing (RAP) was maintained at 600bpm for 2h for paced and Paced+ALS groups and atrial effective refractory periods (AERPs), inducibility of AF (AFi) and average duration time (ADT) were measured. In chronic experiments, there were 5 groups: Sham, Sham+ALS, Paced, Paced+ALS and Paced+ALS+PI3K antagonist wortmannin (WM) (70μgkg-1day-1). RAP at 500 beats/min was maintained for 2weeks. Inflammation and oxidative stress indicators were measured by ELISA assay, echocardiogram and pathology were used to assess atrial structural remodeling, phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/Akt) signaling pathways were studied by RT-PCR and western blotting to evaluate whether the cardioprotective effect of ALS works through PI3K/Akt signaling pathway. The electrophysiological changes were observed after 2-h pacing. The AERP shortened with increased AFi and ADT, which was attenuated by ALS (P < 0.05). After pacing for 2weeks, oxidative stress and inflammation markers in the Paced group were significantly higher than those in the Sham group (P < 0.01) and were reduced by ALS treatment (P < 0.01). The reduced level of antioxidant enzymes caused by RAP was also found to be elevated in ALS-treated group (P < 0.01). The results of pathology and echocardiography showed that RAP can cause atrial enlargement, fibrosis (P < 0.01), and were attenuated in ALS treatment group. The PI3K/Akt signaling pathway were downregulated induced by RAP. ALS could upregulate the PI3K/Akt pathway expression (P < 0.05). Furthermore, the cardioprotective effects in structural remodeling of ALS were suppressed by WM. ALS may offer cardioprotection in RAP-induced atrial remodeling, which may partly be ascribed to its anti-inflammatory and anti-oxidative stress action and the regulation of PI3K/Akt signaling pathway.

Assessing Atrial Fibrillation Substrates by P Wave Analysis: A Comprehensive Review

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pharmacologic and non-pharmacologic rhythm control strategies impact on AF-related symptoms, while leaving largely unaffected the risk of stroke. Moreover, up to 20% of AF patients are asymptomatic during paroxysmal relapses of arrhythmia, thus underlying the need for early markers to identify at-risk patients and prevent cerebrovascular accidents. Indeed, non-invasive assessment of pre-clinical substrate changes that predispose to AF could provide early identification of at-risk patients and allow for tailored care paths. ECG-derived P wave analysis is a simple-to-use and inexpensive tool that has been successfully employed to detect AF-associated structural and functional atrial changes. Beyond standard electrocardiographic techniques, high resolution signal averaged electrocardiography (SAECG), by recording microvolt amplitude atrial signals, allows more accurate analysis of the P wave and possibly AF risk stratification. This review focuses on the evidence that support P wave analysis to assess AF substrates, predict arrhythmia relapses and guide rhythm-control interventions.

How, When, and Why: High-Density Mapping of Atrial Fibrillation.

High-density (HD) mapping presents opportunities to enhance delineation of atrial fibrillation (AF) substrate, improve efficiency of the mapping procedure without sacrificing safety, and afford new mechanistic insights regarding AF. Innovations in hardware, software algorithms, and development of novel multielectrode catheters have allowed HD mapping to be feasible and reliable. Patients to particularly benefit from this technology are those with paroxysmal AF in setting of preexisting atrial scar, persistent AF, and AF in the setting of complex congenital heart disease. The future will bring refinements in automated HD mapping including evolution of noncontact methodologies and artificial intelligence to supplant current techniques.

Isoproterenol Increases Left Atrial Fibrosis and Susceptibility to Atrial Fibrillation by Inducing Atrial Ischemic Infarction in Rats

Left atrial (LA) fibrosis is a major arrhythmogenic substrate for atrial fibrillation (AF). The purpose of this study was to assess whether isoproterenol (ISO) induces LA fibrosis and increases susceptibility to AF, exploring the underlying mechanisms. Male Sprague-Dawley rats were subcutaneously injected ISO once per day for 2 days. Five weeks after injection, the ISO group had higher susceptibility AF and prolonged AF duration compared with the control group. ISO decreased LA conduction velocity (CV) and increased LA conduction heterogeneity. ISO increased fibrosise areas and the protein levels of collagen types I and III in the left atrium. Antifibrosis drug pirfenidone decreased AF occurrence and reduced LA fibrosis in ISO treated rats. ISO injection induced atrial ischemia infarction by increasing heart rate and decreasing diastolic and systolic blood pressures. These findings demonstrated that ISO increases susceptibility to AF by increasing LA fibrosis and LA conduction abnormalities 5 weeks after injection. ISO injection induces atrial ischemic injury is the main cause of fibrosis. Rats with ISO-induced LA fibrosis may be used in further AF research.

Left atrial fibrosis progression detected by LGE-MRI after ablation of atrial fibrillation.

Left atrial (LA) fibrosis is thought to be a substrate for atrial fibrillation (AF) and can be quantified by late gadolinium enhancement magnetic resonance imaging (LGE-MRI). Fibrosis formation in LA is a dynamic process and may either progress or regress following AF ablation. We examined the impact of postablation progression in LA fibrosis on AF recurrence. LA enhancement in LGE-MRI was quantified in 127 consecutive patients who underwent first time AF ablation. Serial LGE-MRIs were done prior to AF ablation, 3 months postablation and at least 12 months after second LGE-MRI. Transient postablation lesion (TL) was defined as atrial enhancement caused by ablation lesions that was detected on the first (3 month) but not on the second postablation LGE-MRI. New fibrosis (NF) was defined as atrial enhancement detected on the most recent LGE-MRI, at least 15 months after the ablation procedure. AF recurrence and its correlation with TL and NF was assessed in all patients during the follow-up period. An increase of 1% NF increased the chance of postablation AF recurrence by 3% (hazard ratio [HR] 1.03, 95% CI 1-1.06, P=.05). TL had no significant impact on recurrence (P=.057). After adjusting for cardiovascular risk factors, HR increased as NF became greater. Greater volume of NF (≥21%) corresponded with lower arrhythmia-free survival (37%vs 62%, P=.01). NF formation postablation of AF is a novel marker of long-term procedural outcome. Extensive NF is associated with significantly higher risk of atrial arrhythmia recurrence.

Peripherally Restricted Dual Cannabinoid Receptor Agonist Modifies Mitochondrial Signaling and Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

Atrial fibrillation (AF) leads to rate‐dependent changes, which progressively increase the risk for recurrence and persistence of the arrhythmia (collectively defined as atrial remodelling). Atrial effective refractory period (AERP) shortening and conduction velocity prolongation are hallmarks of atrial remodelling markedly promoting AF substrate. The molecular mechanisms underlying atrial remodelling are not fully elucidated and therapeutic strategies to reduce AF burden by preventing atrial remodelling are not yet available. Cannabinoid (CB) receptor ligands exert cardioprotective effects. We hypothesized that CB13, a peripherally restricted dual CB receptor agonist with limited brain penetration, would reduce atrial remodelling.Sprague Dawley (SD) rat hearts were excised and hung on a Langendorff set‐up, and supplemented with CB13 (1μM) or without (control) (paced and non‐paced). Coronary pressure of 60–80 mmHg was maintained. Electrophysiological (EP) parameters were measured by placing a mini‐hook platinum‐iridium quadrupole electrode on the right atrium (RA) for pacing and atrial recording (CB13 n=8; control n=8). RA were tachypaced for 90 min at double diastolic threshold and a cycle length of 5 ms higher than failed 1:1 atrial capture. S1S2 stimulation protocol was used to measure AERP, defined as the longest interval with failed 1:1 capture. The effects of CB13 on atrial refractoriness and AF substrate were assessed by analysis of high resolution electrogram recordings and protein expression via western blot.Post‐tachypacing EP recordings showed reduced AERP in control compared to pre‐tachypacing (54.38±3.05 vs. 44.75±3.67 ms; p&lt;0.01). AERP post‐tachypacing in CB13‐treated hearts remained unchanged compared to pre‐tachypacing (55.25±3.46 vs. 55.50±2.67 ms; ns). Thus, CB13‐treatment resulted in preservation of AERP compared to control (103.6±9.2 vs. 82.3±4.4 % of baseline; p&lt;0.05). Protein expression of PGC1α was significantly increased by CB13 compared to controls (paced and non‐paced). Upregulation of mitochondrial biogenesis may be related to increased phosphorylation of AMPKα at residue threonine 172 (compared to total AMPKα, p=0.12, CB13 vs. control paced). Furthermore, gap junction connexin 43 was significantly downregulated in paced controls vs. non‐paced controls, while CB13 remained upregulated (no significance vs. controls).CB13 exposure during tachypacing prevents AERP reduction and gap junction downregulation probably through mechanisms involving mitochondrial biogenesis. Thus, by inhibiting atrial remodeling CB13 and the subsequent activation of CB receptors may be a viable treatment strategy for AF.Support or Funding InformationThis work was supported by studentships from the Canadian Institutes of Health Research and Mitacs (D.L.)

Chronic Atrial Overload Contributes to the Slow Decay of Intramural Fibrosis in the Human Atrium: Assessment by High‐Resolution 3D Histology

BackgroundThe intramural distribution of fibrosis is considered one of the most important factors in the formation of a substrate for atrial fibrillation. Chronic atrial stretch is known to play a mechanistic role in this structural remodeling process. However, the distribution of fibrosis through the entire atrial wall is poorly characterized as well as its relationship with chronic atrial stretch. Based on these premises, this study aimed at assessing the intramural profile of fibrosis in the human atrium in patients with different degrees of atrial dilatation and arrhythmic profiles by high‐resolution 3D histology.Methods and ResultsSerial vibratome‐cut longitudinal slices, encompassing the whole atrial wall at a resolution of 5 μm, were obtained from right atrial appendage samples from cardiac surgery patients. Serial slices were stained in Picrosirius red, imaged by polarized light microscopy, and analyzed with a custom‐made computer program. In all patients the intramural fibrotic content followed a progressive decreasing profile along tissue depth, passing from the epicardium to the endocardium. On average it decreased from 69 ± 12 % to 34 ± 16 % within the first 20% of atrial tissue depth, undergoing a further slight decrease to 21 ± 14 % at 40% of tissue depth. Finally, in deeper mid‐wall to subendocardial layers, the average fibrotic content slightly varied around low values of 10–13%. Distinct intramural fibrotic profiles were observed in sinus rhythm patients with normal atria with respect to patients with dilated atria, who showed, respectively, rapid and slow exponential decays (decay constant: 80.9 ± 24.4 μm versus 171.2 ± 54.5 μm, p&lt;0.005). Similar to patients with atrial dilatation, patients with atrial fibrillation showed a slow fibrotic decrease with decay constant of 142.9 ± 41.7 μm. The decay rate of intramural fibrosis correlated with the degree of atrial dilatation (r=0.69, p&lt;0.001).ConclusionsThe quantification of the intramural profile of fibrosis in the human atrium is feasible by combining slice‐to‐slice histology with computerized image analysis. Our results showed a deeper penetration of fibrosis in the atrial wall closely related with the presence of atrial dilatation. The stretch‐related intramural penetration of fibrosis may contribute to epiendocardial dissociation of electrical activity and the formation of an arrhythmic substrate.Support or Funding InformationThis work was supported by Fondazione Cassa di Risparmio di Trento e Rovereto.