Abstract Atrial Fibrillation Research Articles

Extent of self-adjustment to AF in exercise capacity evaluates significance of sinus maintenance and determines suitability of sinus maintenance therapy in patients with persistent AF

Abstract Atrial fibrillation (AF) causes hemodynamic inefficiency and possibly deteriorates to heart failure (HF). However, we have experienced drastic variances in the extent of HF deterioration in persistent AF (PeAF) patients. Some studies showed that newly developed PeAF (New AF), not preexisting PeAF adversely impacted HF patients in two years. These issues suggest that most PeAF patients gradually adjust to AF-induced hemodynamic inefficiency, however the extent of self-adjustment to PeAF differs among patients. We hypothesized that the extent of the self-adjustment might determine the adverse impact of New AF on patients. We proposed that especially New AF patients with poor adjustment to PeAF should be targeted for aggressive sinus rhythm (SR) maintenance through catheter ablation (RFCA). We considered exercise capacity (EC) of PeAF patients as the extent of the self-adjustment to PeAF. Consequently, we sought to investigate whether EC testing (CPX) in PeAF patients could be used as a determinant for suitability of aggressive SR maintenance therapy in PeAF patients. Subjects & Method: We performed CPX to evaluate Peak VO2 intake (PVO2) at baseline for 196 consecutive PeAF patients undergoing RFCA (male: 151, female: 45). After >6 months SR-maintenance, CPX was repeated. %PVO was calculated by standardizing PVO to age and gender. During RFCA, Swan-Ganz catheter study was done to monitor changes in hemodynamics before and after RFCA. Echocardiography was done at baseline, 6 months after SR maintenance. Results %PVO varied from 38 to 175% before RFCA. %POV2 of NYHA 3 class patients was 76.8±17.7%. PeAF patients with 80% and more of %PVO2 seemed adjusted to AF in terms of exercise capacity. In this study we defined PeAF patients below 80% PVO2 as Non-adjusted. Out of 196 patients, 149 undertook CPX again. Changes in %PVO2 ranged from −38% to 48% (median: 7.0%). According to multi-regression analysis of changes in %PVO, PeAF patients with Non-adjustment (β=0.31), greater increase in HR during repeated CPX (β=0.40), larger reduction in E/e (β=−0.21) after SR maintenance, obtained larger improvement in EC. Particularly, Non-AF adjustment in PeAF patients was the sole predictor of improvement in EC after RFCA. Furthermore, we sought to identify the determinants of Non-AF adjustment in PeAF patients. Multivariate logistic analysis demonstrated that female patients became Non-adjusted significantly more easily than male (p<0.001). Increase in HR during CPX was the most important factor for adjustment to PeAF. In males, poor LV diastolic function, higher Pulmonary vascular resistance were also negative predictors for adjustment to PeAF. However, there is concern about deterioration in EC for patients with chronotropic incompetence revealed after RFCA. Conclusion The extent to which PeAF patients could adjust to AF helps in evaluating the significance of SR-maintenance and determining the suitability of aggressive SR-maintenance therapy. Funding Acknowledgement Type of funding source: None

What is the prognosis for patients who develop new-onset atrial fibrillation in the first 48 hours after an acute coronary syndrome?

Abstract Atrial fibrillation (AF) is a common complication in acute coronary syndrome (ACS). However, treating patients (pts) with new-onset AF (NOAF) after an ACS remains a challenge. Although it seems intuitive that pts who develop AF within the first 48h have increased morbidity and mortality, your prognosis is unclear because there are no robust studies in the literature to confirm this association. Aim To characterize the population of pts who developed NOAF in the first 48 hours after an ACS and to compare the prognosis between these pts and pts who didn't develop AF. Methods 2916 ACS pts admitted consecutively in our coronary care unit during 6 years were analyzed retrospectively. Of these pts, 343 (11.7%) had AF within the first 48h, of which 99 (3.4%) had pre-existing AF and 243 (8.3%) presented NOAF. Pts were divided into two groups: group 1 -ACS pts who developed NOAF in the first 48h (n=243; 8.8%); group 2 – ACS pts who did not develop AF (n=2517; 91.2%). Pts with pre-existing AF were excluded (n=156; 5.4%). Primary endpoint were the occurrence of death at 6 months; follow-up was completed in 95.8% of pts. Results Group 1 pts were older (72±12 vs 62±13, p<0.001), with higher proportion of women (30,9% vs 20,9%, p<0.001), hypertensive (78,5% vs 60,7%, p<0.001), smokers (17,4% vs 32,6%, p<0.001), previous CABG (7,9% vs 3,8%, p=0.06) and stroke (10,7% vs 6,8%, p=0.035). Group 1 had a higher proportion of STEMI pts (58,5% vs 46,5%, p<0.001) and, during hospitalization, had more often respiratory infection (p<0.001), malignant arrhythmias (p<0.001), heart failure (p<0.001), stroke (p=0.001), higher values of NT-proBNP (p<0.001) increased C-reactive protein levels (p<0.001), leukocytes (p=0.020), peak of TropI (p=0.029) and creatinine (p<0.001). On echocardiography, group1 had greater LA diameter (45±6 VS 41±5mm, p<0.001), more frequent significant mitral regurgitation (13,9% vs 2,9%, p<0.001), worst LVEF (41±10% vs 46±10%, p<0.001) and a higher value of pulmonary artery pressure (39±12 vs 24±10, p<0.001). Group 1 were less likely to have undergone coronary revascularization (84% vs 74%, p=0.005). In multivariate analysis, age ≥75 (OR 1.05, p<0.001), LVEF ≤40% (OR 2.50, p<0.001), LA diameter (OR 1.59, p=0.027), more significant mitral regurgitation (OR 2.49, p=0.001) and Killip class >1 (OR 1.51, p=0.015) remained independent predictors of NOAF. In multivariate analysis and after adjusting for different baseline characteristics, pts with NOAF have the same risk of 6-months mortality compared to those who didn't develop AF [OR 1.03, p=0.91]. Conclusion The incidence of NOAF was 8.8% in our population, which is similar to the literature. Age, LVEF, LA diameter, a significant mitral regurgitation and Killip class >1 were independent predictors of NOAF after ACS. Pts with NOAF in the first 48h after an ACS had worse clinical manifestations during hospitalization but no higher 6-months mortality risk. Funding Acknowledgement Type of funding source: None

Prediction of mortality and mode of death by clinical risk score systems in 2.6 million patients with atrial fibrillation: a nationwide analysis

Abstract Atrial fibrillation (AF) is associated with a higher mortality, but modes of death may vary and their respective predictors have been insufficiently defined. Charlson comorbidity index (CCI) is a tool to quantify multimorbidity and a strong estimator of mortality. The quantifiable frailty phenotype is also predictive of mortality and disability and claims data can be used to classify individuals as frail and non-frail using the Claims-based Frailty Index (CFI). We evaluated whether these tools may help to predict mortality and the different modes of death in AF. Methods Based on the France nationwide administrative hospital-discharge database, we collected information for all AF patients treated between 2010 and 2019 in France. Adverse outcomes were investigated during follow-up. CHA2DS2VASc score, CCI and CFI were calculated for each patient. Results Among 2,641,626 patients with AF, 670,541 patients died during a follow-up of 2.0±2.3 years (median 1.1) (yearly rate 12.6%, 30.3% cardiovascular and 69.7% non-cardiovascular deaths). Death occurred more often in patients with higher CHA2DS2VASc, CCI and CFI scores. CCI was a better predictor of total mortality than CFI and CHA2DS2VASc score (see C-statistics in table); however, the CHA2DS2VASc score was a better predictor of cardiovascular mortality than CCI and CFI. By contrast, CCI was a better predictor of non-cardiovascular mortality than CFI and CHA2DS2VASc score. The optimal predictive performances were better for non-cardiovascular death than for cardiovascular death. Conclusion Multimorbidity assessed with CCI demonstrated better performances in predicting total mortality and non-cardiovascular mortality than CHA2DS2VASc score and Frailty assessed with CFI in AF patients. By contrast, CHA2DS2VASc score was a better predictor of cardiovascular mortality than CCI and CFI in these patients. Funding Acknowledgement Type of funding source: None

Early risk of mortality, cardiovascular events, and bleeding in patients with newly diagnosed atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is independently associated with a 1.5- to 2.0-fold higher risk of all-cause death and increased morbidity, in particular for heart failure and stroke. Previous studies have shown that the annual rate of death in AF patients is ∼5%; however, emerging data indicate that the risk of death, but also of thromboembolic and bleeding complications, is highest early after the diagnosis, especially during the first month. In light of these observations, patients with newly diagnosed AF deserve close monitoring and may benefit from a comprehensive care targeting modifiable risk factors for death, such as heart failure, diabetes, renal impairment, and vascular disease. Aim of this report is to focus on timing and causes of death as well as on temporal trends of cardiovascular and bleeding complications in patients with newly diagnosed AF.

Atrial fibrillation in a cohort of patients with peripheral arterial disease. A retrospective study of a healthcare database in UK

Abstract Atrial fibrillation in a cohort of patients with peripheral arterial disease. A retrospective study of a healthcare database in UK. Background There is strong evidence that peripheral arterial disease (PAD) is linked with worse outcomes in patients with atrial fibrillation (AF), which has led vascular disease to be included as one of the components of CHA2DS2-VASc score for risk stratification in AF. On the other hand, very limited evidence exists on the prognostic implication of AF in patients with PAD. Purpose The aim of this study is to identify the prevalence of AF in a cohort of PAD patients and demonstrate its association with adverse cardiovascular outcomes, limb loss and mortality. Methods This is a retrospective study of The Health Improvement Network (THIN) database, which contains computerized records from primary care physicians, covering more than 11 million patients from over 600 general practices in the UK. During the studied period from 1995 to 2017, 55540 patients with newly diagnosed PAD have been detected in the database and baseline characteristics, coexisting medical diagnoses (including AF), relevant medication and subsequent outcomes have been recorded using appropriately selected clinical codes (READ codes). A comparison of baseline characteristics was made between patients with PAD and AF and those without AF using descriptive statistics. Multivariate cox regression analysis was then performed and hazard rations for mortality, stroke or transient ischaemic attack (TIA), ischaemic heart disease (IHD), heart failure (HF) and major lower limb amputation at presence of AF were calculated, after adjustment for age, sex, ethnicity, BMI, smoking, Townsend comorbidity index, diabetes, hypertension, kidney function, and medication (lipid- lowering, antiplatelets, anticoagulants). Results From the 55540 patients with new diagnosis of PAD during the study period, 5685 (10.2%) had coexisting AF. Patients with AF were older, had higher prevalence of diabetes, hypertension and renal failure, were more likely to be on anticoagulants, antiplatelets and lipid lowering agents, were more likely to be ex-smokers but less likely to be active smokers. Mean follow up period was 5.1 (SD= 4) years. After adjustment for confounders, AF patients were at higher risk for death (HR: 1.30, 95% CI 1.24- 1.37, p<0.01) for stroke or TIA (HR: 1.46, 95% CI 1.29- 1.65, p<0.01) and for HF (HR: 1.85, 95% CI 1.65- 2.08, p<0.01). There was no significant association between AF and development of IHD (p=0.34) and limb loss (p=0.14) in this cohort. Conclusion AF is a predictor of worse prognosis in patients with PAD. Close monitoring and medical optimization of these patients is warranted. Funding Acknowledgement Type of funding source: None

Atrial fibrillation ablation in heart failure: What do we know? What can we do?

Atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) are two conditions that frequently impact reciprocally on each other. Patients with HFrEF have an increased risk of stroke, hospitalization and mortality after they develop AF and vice versa, AF causing deterioration of the ejection fraction is also associated to increased mortality. Catheter ablation has emerged as an effective alternative to antiarrhythmic drug treatment to maintain sinus rhythm and some randomized trials have shown a potential benefit in terms of mortality and hospitalization. This review discusses the available evidence regarding catheter ablation treatment in this specific patient group.

Determinants of Use of Long-term Continuous Electrocardiographic Monitoring for Acute Ischemic Stroke Patients without Atrial Fibrillation at Baseline.

Atrial fibrillation (AF) is the most common cardiac rhythm disorder associated with stroke. Increased risk of stroke is the same regardless of whether the AF is permanent or paroxysmal. However, detecting paroxysmal AF is challenging and resource intensive. We aimed to develop a predictive model for AF in patients with acute ischemic stroke, which could improve the detection rate of paroxysmal AF. We analyzed 10,034 adult patients with acute ischemic stroke. Differences in clinical characteristics between the patients with and without AF were analyzed in order to develop a predictive model of AF. The associated factors for AF were analyzed using multivariate logistic regression and classification and regression tree (CART) analyses. We used another dataset, which enrolled 860 acute ischemic stroke patients without AF at baseline, to test whether the developed model could improve the detection rate of paroxysmal AF. Among the study population, 1,658 patients (16.5%) had AF. Multivariate logistic regression revealed that sex, age, body weight, hypertension, diabetes mellitus, hyperlipidemia, pulse rate at admission, respiratory rate at admission, systolic blood pressure at admission, diastolic blood pressure at admission, National Institute of Health Stroke Scale (NIHSS) score at admission, total cholesterol level, triglyceride level, aspartate transaminase level, and sodium level were major factors associated with AF. CART analysis identified NIHSS score at admission, age, triglyceride level, and aspartate transaminase level as important factors for AF to classify the patients into subgroups. When selecting the high-risk group of patients (with an NIHSS score >12 and age >64.5 years, or with an NIHSS score ≤12, age >71.5 years, and triglyceride level ≤61.5 mg/dL) according to the CART model, the detection rate of paroxysmal AF was approximately double in the acute ischemic stroke patients without AF at baseline.

Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation

Atrial fibrillation (AF)–associated remodeling includes contractile dysfunction whose reasons are only partially resolved. Serotonin (5-HT) increases contractile force and causes arrhythmias in atrial trabeculae from patients in sinus rhythm (SR). In persistent atrial fibrillation (peAF), the force responses to 5-HT are blunted and arrhythmic effects are abolished. Since force but not arrhythmic responses to 5-HT in peAF could be restored by PDE3 + PDE4 inhibition, we sought to perform real-time measurements of cAMP to understand whether peAF alters PDE3 + PDE4-mediated compartmentation of 5-HT4 receptor-cAMP responses. Isolated human atrial myocytes from patients in SR, with paroxysmal AF (paAF) or peAF, were adenovirally transduced to express the FRET-based cAMP sensor Epac1-camps. Forty-eight hours later, cAMP responses to 5-HT (100 μM) were measured in the absence or concomitant presence of the PDE3 inhibitor cilostamide (0.3 μM) and the PDE4 inhibitor rolipram (1 μM). We successfully established real-time cAMP imaging in AF myocytes. 5-HT increased cAMP in SR, paAF, and peAF, but in line with previous findings on contractility, this increase was considerably smaller in peAF than in SR or paAF. The maximal cAMP response to forskolin (10 μM) was preserved in all groups. The diminished cAMP response to 5-HT in peAF was recovered by preincubation with cilostamide + rolipram. We uncovered a significantly diminished cAMP response to 5-HT4 receptor stimulation which may explain the blunted 5-HT inotropic responses observed in peAF. Since both cAMP and force responses but not arrhythmic responses were recovered after concomitant inhibition of PDE3 + PDE4, they might be regulated in different subcellular microdomains.

Pathophysiology of atrial fibrillation and chronic kidney disease.

Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related conditions with shared risk factors. The growing prevalence of both AF and CKD indicates that more patients will suffer from concurrent conditions. There are various complex interlinking mechanisms with important implications for the management of these patients. Furthermore, there is uncertainty regarding the use of oral anticoagulation (OAC) in AF and CKD that is reflected by a lack of consensus between international guidelines. Therefore, the importance of understanding the implications of co-existing AF and CKD should not be underestimated. In this review, we discuss the pathophysiology and association between AF and CKD, including the underlying mechanisms, risk of thrombo-embolic and bleeding complications, influence on stroke management, and evidence surrounding the use of OAC for stroke prevention.

Atrial fibrillation and cognitive impairment: cerebral microbleeds as a new risk factor and possibilities of anticoagulant therapy (Part 2)

Atrial fibrillation (AF) and cognitive impairment (CI) are among the most important problems of the modern health care system, which are characterized by an extremely high prevalence with the increasing trend of the latter; they lead to lower quality of life, shorter duration, and a larger number of disabled people. The specific feature of AF and CI is the presence of common risk factors. To date, the data of an increasing number of studies allow cerebral microbleeds (CMBs) to be considered as a new risk factor for CI, inter alia in patients with AF. In recent years, special attention has been paid to the role of oral anticoagulants (OACs) in the prevention of CI in AF, which is reflected in a number of studies and meta-analyses. In terms of the effect of OACs on the risk of CMBs, there is reason to believe that the latter increases with the use of warfarin, the effects of direct OACs (DOAC) in this regard require further investigation. At the same time, among the DOACs, apixaban is the only drug that has been proven to have no negative effect on the risk of CMBs in a randomized controlled clinical trial. In general, the available data indicate the positive effect of OACs in reducing the risk of CI and dementia in AF; moreover, DOACs have an advantage in this respect. Among the DOACs, apixaban is promising due to its optimal efficacy and safety profile.

Adverse remodeling in atrial fibrillation following isolated aortic valve replacement surgery.

Atrial fibrillation (AF) is the most common arrhythmia with adverse clinical outcomes. Aortic valve replacement (AVR) is one of the most frequently performed cardiac surgeries, although there is scarce evidence on arrhythmic outcomes. We aimed to evaluate AF during the first year post- isolated aortic valve replacement surgery and its clinical, analytical, and echocardiographic predictors. Severe aortic stenosis patients with no prior atrial fibrillation submitted to isolated aortic valve replacement surgery were included in our study, of which 316 remained in sinus rhythm and 24 developed AF. We performed logistic regression searching for AF predictors and a longitudinal comparison between pre and post-operative echocardiographic data. Postoperative AF (POAF), diabetes, and follow-up indexed Left Atrium Diameter (iLAD) were significantly higher in the group of patients developing AF. POAF and iLAD were independent AF predictors at follow-up. No differences between groups were found regarding baseline and follow-up echocardiographic data except for indexed Left Ventricle End-diastolic Diameter (LVED), which failed to decrease after surgery in the AF group. POAF and iLAD independently predicted AF at 1 year following isolated AVR surgery in aortic stenosis patients with no AF history. iLVED did not decrease significantly at follow-up in AF patients, possibly reflecting adverse ventricular remodeling.

Experience in screening for atrial fibrillation and monitoring arrhythmia using asingle-lead ECG stick.

Atrial fibrillation (AF) is the most common arrhythmia and is highly associated with increased morbidity and mortality. Since many AF episodes remain subclinical, screening for AF is considered adesirable approach for timely diagnosis, prevention of sequelae and effective treatment. Recently, devices for AF detection-stand-alone or integrated in mobile health technology-have become available and show promising preliminary results in the detection and monitoring of arrhythmia. This review describes the technical aspects of asingle-lead ECG stick and summarizes the current literature, experience in large-scale screening for AF in pharmacies and potential fields of application.

Does Catheter Ablation Lower the Long-Term Risk of Stroke and Mortality in Patients with Atrial Fibrillation? A Concise Review of the Current State of Knowledge.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and carries a significant risk of morbidity and mortality. Multiple trials have highlighted the benefit of catheter ablation over medical therapy in restoring sinus rhythm and improving quality of life. Whether it reduces long-term risk of stroke and mortality is still unclear.We performed a literature search using the PubMed database to review the current state of knowledge regarding the long-term outcomes of stroke and mortality in ablated patients compared to patients who receive medical therapy. Our review mainly consisted of recent randomized controlled trials and large observational studies. Results from large observational studies show that catheter ablation significantly reduces the risk of stroke in high-risk patients and mortality compared to medical therapy. However, randomized controlled trials have only demonstrated a mortality benefit in patients with comorbid systolic heart failure. In patients with paroxysmal AF, ablation therapy significantly limits the progression to persistent AF and has a higher efficacy in restoring sinus rhythm. Maintenance of sinus rhythm is the most important factor associated with lower long term risk of stroke and mortality.Large randomized controlled trials similar to the Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial are still needed to clarify whether catheter ablation is superior over medical therapy in improving the long-term outcomes of stroke and mortality.

Abstract 216: Establishing an Integrated Platform to Validate Genetic Targets Associated With Atrial Remodeling

Atrial fibrillation (AF)–the most common form of arrhythmia in the general population– is a grievous illness and a public health concern of global and epidemic scale. Current pharmacological therapies targeting ion channels or β-receptors are only partially effective and often fail to reduce AF burdens or mortality. We hypothesized that structural atrial remodeling, in addition to electrical remodeling, are key drivers of AF initiation and progression. In order to discover unrecognized drivers of AF mechanisms and reduce attrition rates in drug development, we employed Genome-Wide Association Studies (GWAS) to identify novel targets with human genetic validation. Meta-analyses of multi-ethnic patient cohorts reported 134 genetic loci, and therefore hundreds of coding variants, that are associated with AF. Atrial-specific cardiomyocytes (aCMs) differentiated from induced pluripotent stem cells (iPSCs) offer a human-relevant model system to study atrial remodeling. We combined aCMs with phenotyping platforms like Multi-Electrode Array (MEA) and Traction Force Microscopy (TFM), to evaluate whether unknown genes play a role in either cardiac conductance and/or contraction. We first devised a multi-factorial computational ranking algorithm based on WASPAS to select 50 out of 187 protein-coding targets. Next, we performed a focused loss-of-function phenotypic screen in aCMs to determine their requirement for atrial myocyte function. This resulted in the prioritization of six high value targets with diverse roles in Rho signaling, cell migration, ER stress response and integrin signaling. We also developed efficient CRISPR/Cas9 gene editing of GWAS variants as well as gain-of-function methods in aCMs. The completion of this project will establish an integrated platform for the functional validation of human genetic targets emerging from population studies associated with atrial remodeling.

Abstract 477: Modeling the Effect of TBX5 Downregulation on Human Atrial Conduction Using Induced Pluripotent Stem Cell-derived Cardiomyocytes

Atrial fibrillation (AF) poses a notable healthcare burden due to a high incidence in the increasing population over age 65 and limitations of current treatment approaches. One challenge to effectively treat AF is patient-to-patient heterogeneity in the underlying mechanisms of disease. Therefore, a better understanding of AF pathogenesis and more personalized approaches to therapy could reduce risk of side effects and improve therapeutic efficacy. Genome wide association studies (GWAS) have revealed several candidate genes for AF including TBX5 , which encodes for a transcription factor involved in heart development. While work in animal models suggests that loss of TBX5 promotes atrial arrythmias, experimental evidence in human cells is lacking. We created an in vitro model of human atrial conduction using day 60+ induced pluripotent stem cell-derived atrial-like cardiomyocytes (iPSC-aCMs) differentiated from three established healthy iPSC lines. Over 90% atrial-like purity (out of 350+ alpha-actinin positive cardiomyocytes) could be achieved based on MLC2v-/MLC2a+ immunofluorescent staining. TBX5 knockdown via esiRNA resulted in downregulation of genes related to conduction velocity ( GJA5 and SCN5A ), consistent with an enhanced risk of AF. Single cell optical electrophysiology demonstrated slightly reduced action potential amplitude and upstroke velocity for TBX5 knockdown cells versus GFP esiRNA controls, suggesting a functional effect of SCN5A downregulation. Additionally, microelectrode array studies have revealed a trend towards slowed conduction velocity with TBX5 knockdown compared to GFP esiRNA controls (13.1±3.0 cm/s vs 17.0±3.8 cm/s respectively). By further investigating the functional effects of modulating transcription factors such as TBX5 in iPSC-aCMs, our results provide enhanced insight into the regulation of atrial conduction and identify potential AF-related pathways for therapeutic targeting.

Abstract 418: Caveolar Disruption of L-type Calcium Channel and Ryanodine Receptor Facilitates Atrial Ectopy and Arrhythmogenesis in Heart Failure Mice

Atrial fibrillation (AF) often occurs during heart failure (HF). Ectopic foci that trigger AF, are linked to discrete atrial regions that experience the highest remodeling and clinically used for AF ablation; however, mechanisms of their arrhythmogenic propensity remain elusive. We employed in vivo ECG telemetry, in vitro optical mapping and confocal imaging of Ca 2+ transients (CaT) from myocytes isolated from the right atrial appendage (RAA) and inter-caval region (ICR) of wild type (WT, n=10), caveolin-3 knockout (KO, n=6) and 8-weeks post-myocardial infarction HF (n=8) mice. HF and KO mice showed an increased susceptibility to pacing-induced AF and enhanced ectopy originated exclusively from ICR. Optical mapping in isolated atria showed prolongation of CaT rise up time (CaT-RT) in HF ICR, which suggested a remodeled coupling between L-type Ca 2+ channels (LTCCs) and ryanodine receptors (RyRs) in this specific region. In WT mice, RAA consists of structured myocytes with a prominent transverse-axial tubular system (TATS) while ICR myocytes don’t have TATS. In RAA, CaT-RT depends on LTCCs in TATS triggering RyR, while in ICR, all the LTCCs are localized in surface caveolae where they can activate subsarcolemmal RyRs and lead to a slow diffusion of Ca 2+ inside the cell interior. Downregulation of caveolae was observed specifically in HF ICR. To mimic this, we used cav3-KO mice. Triggered activities were observed in myocytes isolated from HF and KO ICR, which presumably underlie the ectopic activities in tissue level. These myocytes presented significantly unsynchronized sarcoplasmic reticulum (SR) Ca 2+ releases (synchronization index: 10.8±0.9 in WT vs 38.3±4.1 in HF vs 21.5±2.1 in KO, p <0.01 for HF and KO vs WT respectively) especially at the subsarcolemmal space that prolongs CaT-RT (62.2±4.1 ms in WT vs 122.5±12.8 ms in KO, p <0.01). In addition, failing ICR myocytes showed a higher occurrence and size of spontaneous Ca 2+ sparks which were linked to CaMKII activity and associated phosphorylation of RyR. Our findings demonstrate that in HF, caveolar disruption creates “hot spots” for arrhythmogenic ectopic activity emanated from discrete vulnerable regions of the right atrium which are associated with desynchronized SR Ca 2+ release and elevated fibrosis.

Abstract 550: FOG2 Modulates a TBX5-Dependent Gene Regulatory Network for Cardiac Rhythm Homeostasis

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Recent work has implicated numerous transcription factors in AF risk, including ZFPM2 (FOG2), GATA4, and TBX5. FOG2 is overexpressed in human heart failure, a major AF risk factor. We found that genetic inducible physiologic overexpression of FOG2 in the adult mouse heart caused spontaneous atrial fibrillation. Single cell electrophysiology revealed action potential prolongation and inappropriate depolarizations in FOG2-OE atrial cardiomyocytes. RNA-seq of the FOG2-OE left atrium prior to AF onset demonstrated that FOG2 suppresses a network of calcium cycling genes, providing a possible mechanism for disrupted cardiomyocyte electrophysiology. FOG2 ChIP-seq demonstrated genomic localization only at locations co-occupied by GATA4. Unexpectedly, we observed little overlap between genes activated by GATA4 and repressed by FOG2. Instead, we observed highly significant overlap between genes repressed by FOG2 and activated by TBX5. To identify the FOG2-dependent atrial gene regulatory network, we performed differential deep sequencing of ncRNAs. Comparison of atrial FOG2-dependent non-coding transcripts with previously performed TBX5-dependent ncRNA profiling indicated that TBX5 activated and FOG2 repressed a shared atrial rhythm gene regulatory network. Integration of FOG2, GATA4, and TBX5 ChIP-seq revealed that FOG2 only affected ncRNA transcription, indicative of enhancer activity changes, at locations co-occupied by TBX5. TBX5-dependent activation of specific regulatory elements for calcium handling genes was abolished by FOG2 in vitro . The genomic TBX5/FOG2 interaction predicted a genetic interaction in-vivo , in which cardiac conduction and arrhythmia abnormalities caused by Tbx5 haploinsufficiency were rescued by FOG2 haploinsufficiency. Non-coding RNA profiling thereby predicted a novel functional TF interaction between FOG2 and TBX5. This work reveals a specific genomic model of atrial rhythm control in which FOG2 is recruited to GATA4 and TBX5 bound locations to modulate a TBX5-dependent atrial gene regulatory network for calcium handling and cardiac rhythm homeostasis.

Antithrombotic Therapy in Patients with Recent Stroke and Atrial Fibrillation.

Atrial fibrillation (AF) is a common arrhythmia which carries a significant risk of stroke. Secondary prevention, particularly in the acute phase of stroke with anti-thrombotic therapy, has not been validated. The aim of this review is to evaluate the available evidence on the use of antithrombotic therapy in patients with recent stroke who have AF, and suggest a treatment algorithm for the various time points, taking into account both the bleeding and thrombosis risks posed at each stage.

Predictors of Outcomes in Patients with Atrial Fibrillation: What Can Be Used Now and What Hope Is in the Future

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia affecting over 30 million patients worldwide with astronomical figures for progression over the next few decades. In this comprehensive review, we have sought to accumulate the factors that determine outcomes of AF. Patient factors such as age, sex, and ethnicity have a vital impact on the incidence and progression of AF, including outcomes of catheter ablation. While the above are non-modifiable, we also provide detailed associations of potentially modifiable comorbidities such as hypertension, congestive heart failure, valvular heart disease, diabetes mellitus, obesity, obstructive sleep apnea, conduction system disorders, and substance abuse with AF. Beyond patient factors, some parameters related to the AF itself can determine outcomes—such as duration of AF, whether it is paroxysmal or persistent AF and certain critical electrocardiographic patterns that suggest a higher risk of AF recurrence. Imaging modalities such as echocardiography, computed tomography, and cardiac magnetic resonance provide invaluable insights into the progression of AF. We describe the various pharmacological and non-pharmacological strategies for AF management with a peek at some futuristic approaches. While each one of these variables could lend themselves for a separate review, we attempted to provide an overview of the most critical predictors of AF outcomes to equip the readers with the latest know-how of the management of AF.

Multi-scale Entropy Evaluates the Proarrhythmic Condition of Persistent Atrial Fibrillation Patients Predicting Early Failure of Electrical Cardioversion.

Atrial fibrillation (AF) is nowadays the most common cardiac arrhythmia, being associated with an increase in cardiovascular mortality and morbidity. When AF lasts for more than seven days, it is classified as persistent AF and external interventions are required for its termination. A well-established alternative for that purpose is electrical cardioversion (ECV). While ECV is able to initially restore sinus rhythm (SR) in more than 90% of patients, rates of AF recurrence as high as 20–30% have been found after only a few weeks of follow-up. Hence, new methods for evaluating the proarrhythmic condition of a patient before the intervention can serve as efficient predictors about the high risk of early failure of ECV, thus facilitating optimal management of AF patients. Among the wide variety of predictors that have been proposed to date, those based on estimating organization of the fibrillatory (f-) waves from the surface electrocardiogram (ECG) have reported very promising results. However, the existing methods are based on traditional entropy measures, which only assess a single time scale and often are unable to fully characterize the dynamics generated by highly complex systems, such as the heart during AF. The present work then explores whether a multi-scale entropy (MSE) analysis of the f-waves may provide early prediction of AF recurrence after ECV. In addition to the common MSE, two improved versions have also been analyzed, composite MSE (CMSE) and refined MSE (RMSE). When analyzing 70 patients under ECV, of which 31 maintained SR and 39 relapsed to AF after a four week follow-up, the three methods provided similar performance. However, RMSE reported a slightly better discriminant ability of 86%, thus improving the other multi-scale-based outcomes by 3–9% and other previously proposed predictors of ECV by 15–30%. This outcome suggests that investigation of dynamics at large time scales yields novel insights about the underlying complex processes generating f-waves, which could provide individual proarrhythmic condition estimation, thus improving preoperative predictions of ECV early failure.