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Atrial fibrillation (AF) is the most common sustained clinical arrhythmia, with a lifetime incidence of up to 37%, and is a major contributor to population morbidity and mortality. Important components of AF management include control of cardiac rhythm, rate, and thromboembolic risk. In this narrative review article, we focus on rhythm-control therapy. The available therapies for cardiac rhythm control include antiarrhythmic drugs and catheter-based ablation procedures; both of these are presently neither optimally effective nor safe. In order to develop improved treatment options, it is necessary to use preclinical models, both to identify novel mechanism-based therapeutic targets and to test the effects of putative therapies before initiating clinical trials. Extensive research over the past 30 years has provided many insights into AF mechanisms that can be used to design new rhythm-maintenance approaches. However, it has proven very difficult to translate these mechanistic discoveries into clinically applicable safe and effective new therapies. The aim of this article is to explore the challenges that underlie this phenomenon. We begin by considering the basic problem of AF, including its clinical importance, the current therapeutic landscape, the drug development pipeline, and the notion of upstream therapy. We then discuss the currently available preclinical models of AF and their limitations, and move on to regulatory hurdles and considerations and then review industry concerns and strategies. Finally, we evaluate potential paths forward, attempting to derive insights from the developmental history of currently used approaches and suggesting possible paths for the future. While the introduction of successful conceptually innovative new treatments for AF control is proving extremely difficult, one significant breakthrough is likely to revolutionize both AF management and the therapeutic development landscape.

Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The mutation p.Lys23Glu in the cohesin protein Shugoshin-1 causes severe heart arrhythmias due to sinoatrial node dysfunction and a debilitating gastrointestinal motility disorder, collectively termed the Chronic Atrial and Intestinal Dysrhythmia Syndrome, linking Shugoshin-1 and pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is the predominant pacemaker ion-channel in the adult heart and carries the majority of the “funny” current, which strongly contributes to diastolic depolarization in pacemaker cells. Here, we study the mechanism by which Shugoshin-1 affects cardiac pacing activity with two cell models: neonatal rat ventricular myocytes and Chronic Atrial and Intestinal Dysrhythmia Syndrome patient-specific human induced pluripotent stem cell derived cardiomyocytes. We find that Shugoshin-1 interacts directly with HCN4 to promote and stabilize cardiac pacing. This interaction enhances funny-current by optimizing HCN4 cell-surface expression and function. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Our work reveals a critical non-canonical, cohesin-independent role for Shugoshin-1 in maintaining cardiac automaticity and identifies potential therapeutic avenues for cardiac pacemaking disorders, in particular Chronic Atrial and Intestinal Dysrhythmia Syndrome., A mutation in Shugoshin-1 causes the Chronic Atrial and Intestinal Dysrhythmia (CAID) Syndrome, but the underlying mechanisms are unknown. Here, the authors show that Shugoshin-1 controls cardiac pacemaker activity by interacting with HCN4 to enhance its cell-surface expression, and that the CAID-Syndrome mutation disrupts cardiac pacemaking by interfering with this important non-canonical interaction.

Despite significant advances in its detection, understanding and management, atrial fibrillation (AF) remains a highly prevalent cardiac arrhythmia with a major impact on morbidity and mortality of millions of patients. AF results from complex, dynamic interactions between risk factors and comorbidities that induce diverse atrial remodelling processes. Atrial remodelling increases AF vulnerability and persistence, while promoting disease progression. The variability in presentation and wide range of mechanisms involved in initiation, maintenance and progression of AF, as well as its associated adverse outcomes, make the early identification of causal factors modifiable with therapeutic interventions challenging, likely contributing to suboptimal efficacy of current AF management. Computational modelling facilitates the multilevel integration of multiple datasets and offers new opportunities for mechanistic understanding, risk prediction and personalized therapy. Mathematical simulations of cardiac electrophysiology have been around for 60 years and are being increasingly used to improve our understanding of AF mechanisms and guide AF therapy. This narrative review focuses on the emerging and future applications of computational modelling in AF management. We summarize clinical challenges that may benefit from computational modelling, provide an overview of the different in silico approaches that are available together with their notable achievements, and discuss the major limitations that hinder the routine clinical application of these approaches. Finally, future perspectives are addressed. With the rapid progress in electronic technologies including computing, clinical applications of computational modelling are advancing rapidly. We expect that their application will progressively increase in prominence, especially if their added value can be demonstrated in clinical trials., Graphical Abstract

Rationale: The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca 2+ regulates gene expression, but the nature and significance of nuclear Ca 2+ -changes in AF are largely unknown. Objective: To elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca 2+ ([Ca 2+ ] Nuc ) and CaMKII (Ca 2+ /calmodulin-dependent protein kinase-II)-related signaling. Methods and Results: Atrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm × 1 week]). [Ca 2+ ] Nuc and cytosolic [Ca 2+ ] ([Ca 2+ ] Cyto ) were recorded via confocal microscopy. Diastolic [Ca 2+ ] Nuc was greater than [Ca 2+ ] Cyto under control conditions, while resting [Ca 2+ ] Nuc was similar to [Ca 2+ ] Cyto ; both diastolic and resting [Ca 2+ ] Nuc increased with AF. IP 3 R (Inositol-trisphosphate receptor) stimulation produced larger [Ca 2+ ] Nuc increases in AF versus control cardiomyocytes, and IP 3 R-blockade suppressed the AF-related [Ca 2+ ] Nuc differences. AF upregulated nuclear protein expression of IP 3 R1 (IP 3 R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca 2+ ] Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP 3 R knockdown with short-interfering RNA directed against IP 3 R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP 3 R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP 3 R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP 3 R1 upregulation and nuclear diastolic Ca 2+ -loading. Conclusions: AF increases atrial-cardiomyocyte nucleoplasmic [Ca 2+ ] by IP 3 R1-upregulation involving miR-26a, leading to enhanced IP 3 R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.

Advances in atrial fibrillation (AF) management, perioperative medicine, and surgical techniques have reignited an interest in postoperative AF (POAF). POAF results from the interaction among subclinical atrial substrate, surgery-induced substrate, and transient postoperative factors. Prophylaxis for POAF after cardiac surgery is well established but the indications for preoperative treatment in noncardiac surgery need further investigation. A rate-control strategy is adequate for most asymptomatic patients with POAF and anticoagulation should be initiated for POAF more than 48 to 72 hours postsurgery. Research is needed to improve evidence-based management of POAF and guide long-term management in view of the substantial late recurrence-rate.

BACKGROUND: The association between binge alcohol ingestion and atrial fibrillation (AF), often termed "holiday heart syndrome", has long been recognized. However, the underlying cellular and molecular mechanisms are unknown.Methods and Results:An experimental model of binge alcohol-induced AF was developed to elucidate the mechanisms linking acute ethanol exposure to changes in ion channel transcription and AF susceptibility. AF-susceptibility during transesophageal electrical stimulation was enhanced 8 h after, but not immediately or 24 h after, acute alcohol intake. T-type calcium channel (TCC) blockade and calcineurin inhibition diminished the AF-promoting effect of ethanol. Long-term (8-24 h) exposure to ethanol augmented TCC isoform-expression (Cav3.1 and Cav3.2) and currents in cardiomyocytes, accompanied by upregulation of the transcription factors, Csx/Nkx2.5 and nuclear factor of activated T-cells (NFAT), in the nucleus, and of phospho-glycogen synthesis kinase 3s (GSK3s) in the cytosol. Inhibition of protein kinase C (PKC) during the 7- to 8-h period following ethanol exposure attenuated susceptibility to AF, whereas acute exposure did not. GSK3s inhibition itself upregulated TCC expression and increased AF susceptibility. CONCLUSIONS: The present study results suggest a crucial role for TCC upregulation in the AF substrate following binge alcohol-drinking, resulting from ethanol-induced PKC-activation that hyperphosphorylates GSK3s to cause enhanced calcineurin-NFAT-Csx/Nkx2.5 signaling. These observations elucidate for the first time the potential mechanisms underlying the clinically well-recognized, but mechanistically enigmatic, "holiday heart syndrome".

Background Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood. Objective The purpose of this study was to explore the electrophysiological substrate for experimental ES. Methods A model was created by inducing chronic complete atrioventricular block in defibrillator-implanted rabbits, which recapitulates QT prolongation, torsades des pointes (TdP), and VF episodes. Results Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle, leading to increased spatial APD dispersion, in rabbits with ES (defined as ≥3 VF episodes/24 h). The maximum APD and its dispersion correlated with the total number of VF episodes in vivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD dispersion, which was less evident after late Na+ current blockade with 10 μM ranolazine. Nonsustained ventricular tachycardia in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The NaV1.8 blocker A-803467 (10 mg/kg, intravenously) attenuated QT prolongation and suppressed epinephrine-evoked TdP. Conclusion A tissue island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES.

Rationale: 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. Objective: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery. Methods and Results: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca 2+ ] 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 Ca 2+ -transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca 2+ -release events and L-type Ca 2+ -current alternans occurred more frequently. CaMKII (Ca 2+ /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 Ca 2+ -content was unchanged in POAF despite greater SR Ca 2+ -leak, with a trend towards increased SR Ca 2+ -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 Ca 2+ -release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca 2+ -uptake are sufficient to reproduce the Ca 2+ -handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β. Conclusions: Preexisting Ca 2+ -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 Ca 2+ -releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Background Atrial flutter (AFL) and atrial fibrillation (AF) are associated with AF-promoting atrial remodeling, but no experimental studies have addressed remodeling with sustained AFL. Objectives This study aimed to define the atrial remodeling caused by sustained atrial flutter (AFL) and/or atrial fibrillation (AF). Methods Intercaval radiofrequency lesions created a substrate for sustained isthmus-dependent AFL, confirmed by endocavity mapping. Four groups (6 dogs per group) were followed for 3 weeks: sustained AFL; sustained AF (600 beats/min atrial tachypacing); AF superimposed on an AFL substrate (AF+AFLs); sinus rhythm (SR) with an AFL substrate (SR+AFLs; control group). All dogs had atrioventricular-node ablation and ventricular pacemakers at 80 beats/min to control ventricular rate. Results Monitoring confirmed spontaneous AFL maintenance >99% of the time in dogs with AFL. At terminal open-chest study, left-atrial (LA) effective refractory period was reduced similarly with AFL, AF+AFLs and AF, while AF vulnerability to extrastimuli increased in parallel. Induced AF duration increased significantly in AF+AFLs and AF, but not AFL. Dogs with AF+AFLs had shorter cycle lengths and substantial irregularity versus dogs with AFL. LA volume increased in AF+AFLs and AF, but not dogs with AFL, versus SR+AFLs. Optical mapping showed significant conduction slowing in AF+AFLs and AF but not AFL, paralleling atrial fibrosis and collagen-gene upregulation. Left-ventricular function did not change in any group. Transcriptomic analysis revealed substantial dysregulation of inflammatory and extracellular matrix-signaling pathways with AF and AF+ALs but not AFL. Conclusions Sustained AFL causes atrial repolarization changes like those in AF but, unlike AF or AF+AFLs, does not induce structural remodeling. These results provide novel insights into AFL-induced remodeling and suggest that early intervention may be important to prevent irreversible fibrosis when AF intervenes in a patient with AFL.

Use of intraprocedural observation and pharmacologic challenges have been proposed as means to differentiate permanent pulmonary vein (PV)-left atrial conduction block from inadequate ablation lesions.The purpose of this study was to determine the prevalence and clinical impact of spontaneous and adenosine-provoked reconnection using contemporary atrial fibrillation (AF) ablation technologies.The CIRCA-DOSE (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration) study enrolled 346 patients with paroxysmal AF and randomized them to contact force-guided radiofrequency ablation (CF-RF) or cryoballoon ablation. Patients underwent provocative testing with adenosine after a 20-minute observation period. All patients received an implantable cardiac monitor for arrhythmia monitoring.Spontaneous reconnection was observed in 5.4% of PVs (71/1318) during the 20-minute postprocedure observation period, and dormant conduction was elicited in 5.7% of PVs (75/1318). Both spontaneous reconnection and dormant conduction were more common after CF-RF compared to cryoballoon ablation (P = .03 and P.0001, respectively). Acute PV reconnection (spontaneous or adenosine-provoked) was associated with a significantly higher incidence of recurrent atrial tachyarrhythmia in the cryoballoon group (hazard ratio [HR] 2.39; 95% confidence interval [CI] 1.44-3.96; P = .0007) but not in the CF-RF group (HR 1.47; 95% CI 0.84-2.58; P = .16). In the absence of acute reconnection, the freedom from recurrent arrhythmia did not differ between groups (HR 0.95; 95% CI 0.6057-1.495; P = .83).Patients without spontaneous or adenosine-provoked reconnection had better outcomes compared to those with acute PV reconnection, suggesting that efforts should be directed toward ensuring an ideal ablation lesion at the first attempt in order to achieve durable PV isolation.

Aims No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial versus associated ventricular arrhythmia to remodeling. This study assessed the roles of atrial arrhythmia versus high ventricular rate in AF-associated remodeling. Methods and results Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-bpm atrial-tachypacing maintaining AF (AF w/o-AVB); atrial-tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80-bpm); 160-bpm ventricular-tachypacing (V160) reproducing the response-rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-bpm (CTL). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF-groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF-groups (w/o-AVB and AF+AVB) and modestly in V160. AF-duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene upregulation only in AF w/o-AVB. Connexin43 gene-expression was reduced only in AF w/o-AVB. An additional group of 240-bpm ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: versus other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF-duration, strongly decreased left-ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation. Conclusions The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodeling and novel considerations for ventricular rate-control. Translational perspective AF often produces a rapid and irregular arrhythmia in both the atria and ventricles. This study evaluates the contributions of AF-induced atrial versus ventricular arrhythmia to atrial remodeling. Each component produced discrete features: AF-induced atrial arrhythmia caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF-induction by premature ectopic beats, conduction slowing and moderate atrial fibrosis; whereas ventricular arrhythmia slightly increased vulnerability, slowed conduction and induced moderate fibrosis without affecting repolarization/refractoriness,. Combined atrial and ventricular arrhythmia abbreviated refractoriness, strongly increased vulnerability and fibrosis and greatly increased AF stability/duration. This work suggests that in the absence of ventricular rate control, the rapid ventricular response can cause AF-promoting atrial remodeling without overt heart failure; further research is needed to clarify the clinical relevance of these findings.

Chronic obstructive pulmonary disease (COPD) is highly prevalent among patients with atrial fibrillation (AF), shares common risk factors, and adds to the overall morbidity and mortality in this population. Additionally, it may promote AF and impair treatment efficacy. The prevalence of COPD in AF patients is high and is estimated to be ∼25%. Diagnosis and treatment of COPD in AF patients requires a close interdisciplinary collaboration between the electrophysiologist/cardiologist and pulmonologist. Differential diagnosis may be challenging, especially in elderly and smoking patients complaining of unspecific symptoms such as dyspnoea and fatigue. Routine evaluation of lung function and determination of natriuretic peptides and echocardiography may be reasonable to detect COPD and heart failure as contributing causes of dyspnoea. Acute exacerbation of COPD transiently increases AF risk due to hypoxia-mediated mechanisms, inflammation, increased use of beta-2 agonists, and autonomic changes. Observational data suggest that COPD promotes AF progression, increases AF recurrence after cardioversion, and reduces the efficacy of catheter-based antiarrhythmic therapy. However, it remains unclear whether treatment of COPD improves AF outcomes and which metric should be used to determine COPD severity and guide treatment in AF patients. Data from non-randomized studies suggest that COPD is associated with increased AF recurrence after electrical cardioversion and catheter ablation. Future prospective cohort studies in AF patients are needed to confirm the relationship between COPD and AF, the benefits of treatment of either COPD or AF in this population, and to clarify the need and cost-effectiveness of routine COPD screening.

Background Sodium-calcium (Ca

Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system has a significant role in the milieu predisposing to the triggers, perpetuators and substrate for atrial fibrillation. It has direct electrophysiological effects and causes alterations in atrial structure. In a significant portion of patients with atrial fibrillation, the autonomic nervous system activity is likely a composite of reflex excitation due to atrial fibrillation itself and contribution of concomitant risk factors such as hypertension, obesity and sleep-disordered breathing. We review the role of autonomic nervous system activation, with focus on changes in reflex control during atrial fibrillation and the role of combined sympatho-vagal activation for atrial fibrillation initiation, maintenance and progression. Finally, we discuss the potential impact of combined aggressive risk factor management as a strategy to modify the autonomic nervous system in patients with atrial fibrillation and to reverse the arrhythmogenic substrate. (c) 2018 Elsevier B.V. All rights reserved.

Postoperative atrial fibrillation (POAF) complicates 20-40% of cardiac surgical procedures and 10-20% of non-cardiac thoracic operations. Typical features include onset at 2-4 days postoperatively, episodes that are often fleeting and a self-limited time course. Associated adverse consequences of POAF include haemodynamic instability, increased risk of stroke, lengthened hospital and intensive care unit stays and greater costs. Underlying mechanisms are incompletely defined but include intraoperative and postoperative phenomena, such as inflammation, sympathetic activation and cardiac ischaemia, that combine to trigger atrial fibrillation, often in the presence of pre-existing factors, making the atria vulnerable to atrial fibrillation induction and maintenance. A better understanding of the underlying mechanisms might enable the identification of new therapeutic targets. POAF can be prevented by targeting autonomic alterations and inflammation. beta-Blocker prophylaxis is the best-established preventive therapy and should be started or continued before cardiac surgery, unless contraindicated. When POAF occurs, rate control usually suffices, and routine rhythm control is unnecessary; rhythm control should be reserved for patients who develop haemodynamic instability or show other indications that rate control alone will be insufficient. In this Review, we summarize the epidemiological and clinical features of POAF, the available pathophysiological evidence from clinical and experimental investigations, the results of prophylactic and therapeutic approaches and the consensus recommendations of various national and international societies.

Arrhythmia-induced cardiomyopathy (AIC) is characterized by left ventricular systolic dysfunction for which the primary cause is arrhythmia. The hallmark of AIC is its reversibility once the arrhythmia is properly controlled. Any tachyarrhythmia can potentially cause AIC (often called "tachycardiomyopathy"), with atrial fibrillation (AF) being by far the most common in clinical practice. The pathophysiological mechanisms underlying AIC need further clarification, but the available evidence, principally from animal models, implicates metabolic dysfunction due to increased oxygen requirements, neurohormonal adaptive mechanisms, and cellular Ca2+ mishandling as important contributors. Tachycardia is a common denominator of most cases of AIC, but other components specific to the patient and the arrhythmia have been implicated. The diagnosis of AIC requires the exclusion of a primary causative role of other conditions such as hypertension, primary cardiomyopathies, and valve disease, which may require specific pharmacological and invasive therapies. Catheter ablation is emerging as a safe and effective alternative to antiarrhythmic medication and has an established role in the management of AIC. Recent studies showing improved cardiac function and mortality rates in patients with heart failure and concomitant AF dramatically illustrate the often-unrecognized scope of AIC and the potential benefits of interventional therapy. Major AF trials do not otherwise focus specifically on AIC, and careful analysis of the literature is necessary to appreciate the clinical characteristics and therapeutic implications. This contemporary review summarizes the current understanding of pathophysiological mechanisms underlying AIC, discusses the clinical implications, and offers a general approach to management, with a particular focus on AF-induced cardiomyopathy.

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.

Given its complexity, the management of atrial fibrillation (AF) has relied increasingly on expert guideline recommendations; however, discrepancies between these professional societies can lead to confusion among practicing clinicians. This article compares the recommendations in the 2019 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS), the 2020 European Society of Cardiology (ESC), and the 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society (CCS/CHRS) AF guidelines. Although many of the recommendations are fundamentally similar, there are important differences among guidelines; specifically, key differences are present in (1) definitions and classification of AF; (2) the role of opportunistic AF detection; (3) symptom and quality-of-life evaluation; (4) stroke-risk stratification and the indication for oral anticoagulation (OAC) therapy; (5) the role of aspirin in prevention of stroke for patients with AF; (6) the antithrombotic regimens employed in the context of coronary artery disease; (7) the role of OAC, and specifically non-vitamin K direct-acting oral anticoagulants (DOACs), in patients with chronic and end-stage renal disease; (8) the target heart rate for patients treated with a rate-control strategy, along with the medications recommended to achieve the heart-rate target; and (9) the role of catheter ablation as first-line therapy or in patients with heart failure. These differences highlight areas of continuing clinical uncertainty in which there are important needs and opportunities for future investigative work.

Inflammation and fibrosis have been implicated in the pathophysiology of atrial fibrillation. Atrial fibrosis causes conduction disturbances and is a central component of atrial remodeling in atrial fibrillation. Cardiac fibroblasts, the cells responsible for fibrosis formation, are activated by inflammatory mediators and growth factors associated with systemic inflammatory conditions. Thus, inflammation contributes to atrial fibrosis; the complex interplay of these maladaptive components creates a vicious cycle of atrial remodeling progression, maintaining atrial fibrillation and increasing thrombogenicity. This review provides up-to-date knowledge regarding inflammation and fibrosis in atrial fibrillation pathophysiology and their potential as therapeutic targets.

Supplemental Digital Content is available in the text., Rationale: Fibrosis promotes the maintenance of atrial fibrillation (AF), making it resistant to therapy. Improved understanding of the molecular mechanisms leading to atrial fibrosis will open new pathways toward effective antifibrotic therapies. Objective: This study aims to decipher the mechanistic interplay between PLK2 (polo-like kinase 2) and the profibrotic cytokine OPN (osteopontin) in the pathogenesis of atrial fibrosis and AF. Methods and Results: Atrial PLK2 mRNA expression was 10-fold higher in human fibroblasts than in cardiomyocytes. Compared with sinus rhythm, right atrial appendages and isolated right atrial fibroblasts from patients with AF showed downregulation of PLK2 mRNA and protein, along with increased PLK2 promotor methylation. Genetic deletion as well as pharmacological inhibition of PLK2 induced profibrotic phenotype conversion in cardiac fibroblasts and led to a striking de novo secretion of OPN. Accordingly, PLK2-deficient (PLK2 knockout) mice showed cardiac fibrosis and were prone to experimentally induced AF. In line with these findings, OPN plasma levels were significantly higher only in patients with AF with atrial low-voltage zones (surrogates of fibrosis) compared with sinus rhythm controls. Mechanistically, we identified ERK1/2 as the relevant downstream mediator of PLK2 leading to increased OPN expression. Finally, oral treatment with the clinically available drug mesalazine, known to inhibit ERK1/2, prevented cardiac OPN overexpression and reversed the pathological PLK2 knockout phenotype in PLK2 knockout mice. Conclusions: Abnormal PLK2/ERK1/2/OPN axis function critically contributes to AF-related atrial fibrosis, suggesting reinforcing PLK2 activity and/or OPN inhibition as innovative targets to prevent fibrosis progression in AF. Mesalazine derivatives may be used as lead compounds for the development of novel anti-AF agents targeting fibrosis.

Obstructive sleep apnea (OSA) creates a complex and dynamic substrate for atrial fibrillation (AF), which is characterized by structural remodeling as a result of long-term OSA as well as transient and acute apnea-associated transient atrial electrophysiological changes. OSA is present in 21% to 74% of patients with AF, and nonrandomized studies suggest that treatment of OSA by continuous positive airway pressure may help to maintain sinus rhythm after electrical cardioversion and improve catheter ablation success rates. Management of OSA in patients with AF requires a close interdisciplinary collaboration between the electrophysiologist/cardiologist and sleep specialists.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans1. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies2. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism3, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.

BACKGROUND: Pulmonary vein (PV) stenosis is a complication of atrial fibrillation (AF) ablation. The incidence of PV stenosis after routine post-ablation imaging remains unclear and is limited to single-centre studies. Our objective was to determine the incidence and predictors of PV stenosis following circumferential radiofrequency ablation in the multicentre Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) trial. METHODS: Patients with symptomatic AF underwent circumferential radiofrequency ablation in one of 13 trial centres. Computed tomographic (CTA) or magnetic resonance (MRA) angiography was performed before ablation and 90 days after ablation. Two blinded reviewers measured PV diameters and areas. PVs with stenosis were classified as severe (> 70%), moderate (50%-70%), or mild (< 50%). Predictors of PV stenosis were identified by means of multivariable logistic regression. RESULTS: A total of 197 patients (median age 59.5 years, 29.4% women) were included in this substudy. PV stenosis was identified in 41 patients (20.8%) and 47 (8.2%) of 573 ablated PVs. PV stenosis was classified as mild in 42 PVs (7.3%) and moderate in 5 PVs (0.9%). No PVs had severe stenosis. Both cross-sectional area and diameter yielded similar classifications for severity of PV stenosis. Diabetes was associated with a statistically significant increased risk of PV stenosis (OR 4.91, 95% CI 1.45-16.66). CONCLUSIONS: In the first systematic multicentre evaluation of post-ablation PV stenosis, no patient acquired severe PV stenosis. Although the results are encouraging for the safety of AF ablation, 20.8% of patients had mild or moderate PV stenosis, in which the long-term effects are unknown.

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

Physical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort.We included 402 406 individuals (52.5% female), aged 40-69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74-0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82-1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64-0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias.The risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.

Atrial fibrillation (AF) alters atrial cardiomyocyte (ACM) Ca(2+) handling, promoting ectopic beat formation. We examined the effects of AF-associated remodeling on Ca(2+)-related action potential dynamics and consequences for AF susceptibility. AF was maintained electrically in dogs by right atrial (RA) tachypacing. ACMs isolated from AF dogs showed increased Ca(2+) release refractoriness, spontaneous Ca(2+) spark frequency, and cycle length (CL) threshold for Ca(2+) and action potential duration (APD) alternans versus controls. AF increased the in situ CL threshold for Ca(2+)/APD alternans and spatial dispersion in Ca(2+) release recovery kinetics, leading to spatially discordant alternans associated with reentrant rotor formation and susceptibility to AF induction/maintenance. The clinically available agent dantrolene reduced Ca(2+) leak and CL threshold for Ca(2+)/APD alternans in ACMs and AF dog right atrium, while suppressing AF susceptibility; caffeine increased Ca(2+) leak and CL threshold for Ca(2+)/APD alternans in control dog ACMs and RA tissues. In vivo, the atrial repolarization alternans CL threshold was increased in AF versus control, as was AF vulnerability. Intravenous dantrolene restored repolarization alternans threshold and reduced AF vulnerability. Immunoblots showed reduced expression of total and phosphorylated ryanodine receptors and calsequestrin in AF and unchanged phospholamban/SERCA expression. Thus, along with promoting spontaneous ectopy, AF-induced Ca(2+) handling abnormalities favor AF by enhancing vulnerability to repolarization alternans, promoting initiation and maintenance of reentrant activity; dantrolene provides a lead molecule to target this mechanism.

Aims Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodelling via a variety of signalling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1-signalling on LA fibroblast (FB) function and its potential role in HF-related atrial remodelling. Methods and results HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP). Epac1-expression decreased in LA-FBs within 12 h (−3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 µM) reduced, whereas the Epac blocker ESI-09 (1 µM) enhanced, collagen expression in LA-FBs. Norepinephrine (1 µM) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The β-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (β2-AR-blocker), but not by CGP (β1-AR-blocker). β-AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the β2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-β1, known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3-inhibitor SIS3. To evaluate effects on atrial fibrosis in vivo, mice subjected to myocardial infarction (MI) received the Epac-activator Sp-8-pCPT or vehicle for 2 weeks post-MI; Sp-8-pCPT diminished LA fibrosis and attenuated cardiac dysfunction. Conclusions HF reduces LA-FB Epac1 expression. Adrenergic activation has complex effects on FBs, with α-AR-activation suppressing Epac1-expression and increasing collagen expression, and β2-AR-activation having opposite effects. Epac1-activation reduces cardiac dysfunction and LA fibrosis post-MI. Thus, Epac1 signalling may be a novel target for the prevention of profibrillatory cardiac remodelling.

We read with interest the insightful comments by Dr. Reiffel on our paper comparing the atrial remodeling consequences of atrial fibrillation (AF) versus atrial flutter (AFL), alone and in combination ([1][1]). It is well-recognized that rapid ventricular rates cause ventricular cardiomyopathy ([2][

The term atrial cardiomyopathy, which has been used sporadically in the medical literature, was recently the subject of a detailed Consensus Document prepared by representatives of the European Heart Rhythm Association, Heart Rhythm Society, Asia-Pacific Heart Rhythm Society, and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia. They discussed aspects of the definition, histopathology, atrial-specific physiology, atrial pathology, impact on arrhythmia occurrence, imaging, mapping, and ablation. Here, the authors consider critically the added clinical value of this concept and its meaningfulness. They review evidence implicating atrial cardiomyopathy as an independent contributor to the risk of stroke associated with atrial fibrillation and as a determinant of arrhythmia progression. The issue of classification is considered and the authors discuss how atrial cardiomyopathic properties might guide stroke prevention, rhythm maintenance, and rate control in atrial fibrillation. Carefully designed clinical trials are needed to evaluate these potential applications, and will ultimately define the value of this terminology.

The data shown in this article are related to the research article entitled “Characterization of Sgo1 expression pattern in developing and adult mouse” (Song et al., 2017) [3]. The article provides novel data on Sgo1 gene expression pattern utilizing Sgo1_LacZ_Knock in mouse line and immunohistochemistry in wild type mice. The data presents Sgo1 expression pattern during development, and in post-developmental proliferative and quiescent tissue. The article describes following tissues: developing heart, neural tube, adult colon, cerebellum, cerebral cortex, liver, and testis. Keywords: Heart development, Intestinal development, Retinal development, SGO1, CAID syndrome, Cohesin

Aims Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis. Methods and results LA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10 mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-β and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-α, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control. Conclusions HF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention.

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with morbidity and mortality. Over the past 2 decades, there have been major advances in understanding AF pathophysiology, but important knowledge gaps, particularly about targetable basic mechanisms, remain. Recent metabolomic and proteomic studies have shown changes in the expression of molecules involved in metabolic pathways in human and experimental AF, indicating a role for metabolic alterations in AF pathophysiology. AF is characterized by irregular high-frequency excitation and contraction that affect atrial energy demands, circulation and oxygen supply, and change the balance between metabolic demand and supply, causing metabolic stress. Here, we review the information available about AF-induced metabolic changes and their pathophysiological contribution. We also discuss the possibilities of developing novel therapeutic strategies that act by modulating cardiac metabolic processes during AF. OA gold

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation (AF) Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in AF management. This 2016 Focused Update deals with: (1) the management of antithrombotic therapy for AF patients in the context of the various clinical presentations of coronary artery disease; (2) real-life data with non-vitamin K antagonist oral anticoagulants; (3) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (4) digoxin as a rate control agent; (5) perioperative anticoagulation management; and (6) AF surgical therapy including the prevention and treatment of AF after cardiac surgery. The recommendations were developed with the same methodology used for the initial 2010 guidelines and the 2012 and 2014 Focused Updates. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards, individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included in the Supplementary Material, and on the CCS Web site. The section on concomitant AF and coronary artery disease was developed in collaboration with the CCS Antiplatelet Guidelines Committee. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF Guidelines recommendations, from 2010 to the present 2016 Focused Update.

Conditions affecting the right heart, including diseases of the lungs and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood.This study sought to determine whether right heart disease promotes atrial arrhythmogenesis in a rat model of pulmonary hypertension (PH) and, if so, to define the underlying mechanisms.PH was induced in male Wistar rats with a single intraperitoneal injection of 60 mg/kg of monocrotaline, and rats were studied 21 days later when right heart disease was well developed. AF vulnerability was assessed in vivo and in situ, and mechanisms were defined by optical mapping, histochemistry, and biochemistry.Monocrotaline-treated rats developed increased right ventricular pressure and mass, along with right atrial (RA) enlargement. AF/flutter was inducible in 32 of 32 PH rats (100%) in vivo and 11 of 12 (92%) in situ, versus 2 of 32 (6%) and 2 of 12 (17%), respectively, in control rats (p 0.001 vs. PH for each). PH rats had significant RA (16.1 ± 0.5% of cross-sectional area, vs. 3.0 ± 0.6% in control) and left atrial (LA: 11.8 ± 0.5% vs. 5.4 ± 0.8% control) fibrosis. Multiple extracellular matrix proteins, including collagen 1 and 3, fibronectin, and matrix metalloproteinases 2 and 9, were up-regulated in PH rat RA. Optical mapping revealed significant rate-dependent RA conduction slowing and rotor activity, including stable rotors in 4 of 11 PH rats, whereas no significant conduction slowing or rotor activity occurred in the LA of monocrotaline-treated rats. Transcriptomic analysis revealed differentially enriched genes related to hypertrophy, inflammation, and fibrosis in RA of monocrotaline-treated rats versus control. Biochemical results in PH rats were compared with those of AF-prone rats with atrial remodeling in the context of left ventricular dysfunction due to myocardial infarction: myocardial infarction rat LA shared molecular motifs with PH rat RA.Right heart disease produces a substrate for AF maintenance due to RA re-entrant activity, with an underlying substrate prominently involving RA fibrosis and conduction abnormalities.

Aims Age-induced changes and electrical remodelling are important components of the atrial fibrillation (AF) substrate. To study regional distribution and age-dependent changes in gene expression that may promote AF in human atria. Methods and results Human left atrial (LA) and right atrial (RA) tissue samples were obtained from donor hearts unsuitable for transplantation and from patients undergoing mitral valve repair. Atrial fibrillation was mimicked in vitro by tachypacing of human atrial tissue slices. Ionic currents were studied by the whole-cell patch-clamp technique; gene expression was analysed by real-time qPCR and immunoblotting. Both healthy RA and RA from older patients showed greater CACNA1c mRNA and CaV1.2 protein expression than LA. No age-dependent changes of Kir2.1 expression in both atria were seen. Remodelling occurred in a qualitatively similar manner in RA and LA. IK1 and Kir2.1 protein expression increased with AF. MiR-1, miR-26a, and miR-26b were down-regulated with AF in both atria. ICa,L was decreased. CACNA1c and CACNA2b expression decreased and miR-328 increased in RA and LA during AF. Ex vivo tachypacing of human atrial slices replicated these findings. There were age-dependent increases in miR-1 and miR-328, while miR-26a decreased with age in atrial tissues from healthy human donor hearts. Conclusion Features of electrical remodelling in man occur in a qualitatively similar manner in both human atria. Age-related miR-328 dysregulation and reduced ICa,L may contribute to increased AF susceptibility with age.