Atrial fibrillation (AF) is one of the most common arrhythmias encountered in clinical practice. AF is a major risk factor for stroke, which is associated with high mortality and great disability and causes a significant burden on society. With the development of catheter ablation, AF has become a treatable disease, but its therapeutic outcome has been limited so far. In persistent and long-standing AF, the expanded AF substrate is difficult to treat only by ablation, and a better understanding of the mechanism of AF substrate formation will lead to the development of a new therapeutic strategy for AF. Inflammation is known to play an important role in the substrate formation of AF. Inflammation causes and accelerates the electrical and structural remodeling of the atria via pro-inflammatory cytokines and other inflammatory molecules, and enhances the AF substrate, leading to the maintenance of AF and further inflammation, which forms a vicious spiral, so-called “AF begets AF”. Breaking this vicious cycle is expected to be a key therapeutic intervention in AF. In this review, we will discuss the relationship between AF and inflammation, the inflammatory molecules included in the AF-related inflammatory process, and finally the potential of those molecules as a therapeutic target.

Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human. Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations. IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.

BACKGROUND: The circuit boundaries for reentrant ventricular tachycardia (VT) have been historically conceptualized within a 2-dimensional (2D) construct, with their fixed or functional nature unresolved. This study aimed to examine the correlation between localized lines of conduction block (LOB) evident during baseline rhythm with lateral isthmus boundaries that 3-dimensionally constrain the VT isthmus as a hyperboloid structure. METHODS: A total of 175 VT activation maps were correlated with isochronal late activation maps during baseline rhythm in 106 patients who underwent catheter ablation for scar-related VT from 3 centers (42% nonischemic cardiomyopathy). An overt LOB was defined by a deceleration zone with split potentials (≥20 ms isoelectric segment) during baseline rhythm. A novel application of pacing within deceleration zone (≥600 ms) was implemented to unmask a concealed LOB not evident during baseline rhythm. LOB identified during baseline rhythm or pacing were correlated with isthmus boundaries during VT. RESULTS: Among 202 deceleration zones analyzed during baseline rhythm, an overt LOB was evident in 47%. When differential pacing was performed in 38 deceleration zones without overt LOB, an underlying concealed LOB was exposed in 84%. In 152 VT activation maps (2D=53, 3-dimensional [3D]=99), 69% of lateral boundaries colocalized with an LOB in 2D activation patterns, and the depth boundary during 3D VT colocalized with an LOB in 79%. In VT circuits with isthmus regions that colocalized with a U-shaped LOB (n=28), the boundary invariably served as both lateral boundaries in 2D and 3D. Overall, 74% of isthmus boundaries were identifiable as fixed LOB during baseline rhythm or differential pacing. CONCLUSIONS: The majority of VT circuit boundaries can be identified as fixed LOB from intrinsic or paced activation during sinus rhythm. Analysis of activation while pacing within the scar substrate is a novel technique that may unmask concealed LOB, previously interpreted to be functional in nature. An LOB from the perspective of a myocardial surface is frequently associated with intramural conduction, supporting the existence of a 3D hyperboloid VT circuit structure. Catheter ablation may be simplified to targeting both sides around an identified LOB during sinus rhythm.

Background: Recent studies have reported the association between pericoronary inflammation assessed by pericoronary adipose tissue attenuation (PCATA) on computed tomography angiography and worse outcomes in patients with coronary artery disease. We investigated the determinants predicting increased PCATA in patients with known or suspected coronary artery disease. Methods and Results: A total of 540 patients who underwent computed tomography angiography and invasive coronary angiography were studied. Mean computed tomography attenuation values of PCAT (−190 to −30 Hounsfield units) (PCATA) were assessed at the proximal 40‐mm segments of all 3 major coronary arteries by crude analysis. Univariable and multivariable analyses were performed to determine the predictors of increased PCATA surrounding the proximal right coronary artery. Mean right coronary artery‐PCATA was −72.22±8.47 Hounsfield units and the average of 3‐vessel PCATA was −70.24±6.60 Hounsfield units. Multivariable linear regression analysis revealed that the independent determinants of right coronary artery‐PCATA were male (β coefficient=4.965, P 50%) (β coefficient=2.418, P =0.008). Sex‐related determinants were NT‐proBNP level (N‐terminal pro‐B‐type natriuretic peptide; β coefficient <0.001, P =0.026), Agatston score (β coefficient=−0.002, P =0.010), left ventricular mass index (β coefficient=0.041, P =0.028), and significant stenosis (β coefficient=4.006, P <0.001) in male patients and left ventricular ejection fraction (β coefficient=−0.217, P =0.010) and significant stenosis (β coefficient=3.835, P =0.023) in female patients. Conclusions: Right coronary artery‐PCATA was associated with multiple clinical characteristics, established risk factors, and the presence of significant stenosis. Our results suggest that clinically significant factors such as sex, left ventricular hypertrophy, ejection fraction, calcification, and epicardial stenosis should be taken into account in the assessment of pericoronary inflammation using computed tomography angiography.

Atrial inflammation is critical to atrial fibrillation initiation and progression. Although left atrial dilatation is a risk factor for atrial fibrillation, the mechanism linking atrial dilatation and inflammation is unclear. We evaluated the mechanisms underlying infiltration of macrophages induced by stretch of atrial myocytes. Murine macrophages were co-cultured with HL-1 murine atrial myocyte–derived cells. Mechanical stretch applied to atrial myocytes induced transwell macrophage migration. The gap junction–channel blocker carbenoxolone and the non-specific ATP-signaling modifiers apyrase and pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate inhibited the enhanced migration. Mechanical stretch of atrial myocytes induced transient increase in extracellular ATP concentration, which was inhibited by carbenoxolone. siRNA knockdown of pannexin-2 inhibited ATP release and macrophage migration. Mice underwent transverse aortic constriction or sham procedure. Transverse aortic constriction procedure induced macrophage infiltration. Daily carbenoxolone administration significantly inhibited macrophage infiltration in the atrium. Thus, mechanical stretch of atrial myocytes induces macrophage migration by ATP released through gap-junction channels, at least in part, in vitro. Administering a gap junction family–channel blocker inhibited this inflammatory change in vivo.