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Science (New York, N.Y.) Jul 2023Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation....
Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting reduced atrial fibrillation in HOMER mice. These results identify SPP1 macrophages as targets for immunotherapy in atrial fibrillation.
Topics: Animals; Humans; Mice; Atrial Fibrillation; Heart Atria; Macrophages; Mitral Valve Insufficiency; Osteopontin; Gene Deletion; Cell Movement; Single-Cell Gene Expression Analysis
PubMed: 37440641
DOI: 10.1126/science.abq3061 -
The Journal of Clinical Investigation Oct 2023Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main...
Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1β levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3-/- mice or neutralizing anti-IL-1β antibodies effectively reduced IL-1β levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1β antibodies may be beneficial in preventing CKD-induced AF.
Topics: Humans; Mice; Animals; Inflammasomes; Atrial Fibrillation; NLR Family, Pyrin Domain-Containing 3 Protein; Renal Insufficiency, Chronic; Heart Atria; Interleukin-1beta
PubMed: 37581942
DOI: 10.1172/JCI167517 -
European Heart Journal Sep 2023This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation.
BACKGROUND AND AIMS
This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation.
METHODS AND RESULTS
Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P = .014, P < .001, P < .001, and P = .002, respectively) and VGLA (P = .010, P < .001, P = .001, and P < .001, respectively). The intercellular space was associated with the %Fractionated EGM (P = .001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P = .028, P < .001, and P = .015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration.
CONCLUSION
Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.
Topics: Humans; Female; Middle Aged; Aged; Atrial Fibrillation; Electrophysiologic Techniques, Cardiac; Heart Atria; Heart Rate; Fibrosis; Atrial Remodeling; Catheter Ablation
PubMed: 37350738
DOI: 10.1093/eurheartj/ehad396 -
Circulation Aug 2023Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger...
BACKGROUND
Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF.
METHODS
Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization.
RESULTS
A common autoantibody response against K3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. K3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K current, . Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-K3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of , both key mediators of AF. To establish a causal relationship, we developed a mouse model of K3.4 autoimmunity. Electrophysiological study in K3.4-immunized mice showed that K3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF.
CONCLUSIONS
To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of K3.4 autoantibody-mediated AF.
Topics: Humans; Animals; Mice; Atrial Fibrillation; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Induced Pluripotent Stem Cells; Heart Atria; Autoantibodies
PubMed: 37401487
DOI: 10.1161/CIRCULATIONAHA.122.062776 -
Redox Biology Jun 2023Atrial remodeling is a major contributor to the onset of atrial fibrillation (AF) after myocardial infarction (MI). Tripartite motif-containing protein 21 (TRIM21), an...
Atrial remodeling is a major contributor to the onset of atrial fibrillation (AF) after myocardial infarction (MI). Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin protein ligase, is associated with pathological cardiac remodeling and dysfunction. However, the role of TRIM21 in postmyocardial infarction atrial remodeling and subsequent AF remains unclear. This study investigated the role of TRIM21 in post myocardial infarction atrial remodeling using TRIM21 knockout mice and explored the underlying mechanisms by overexpressing TRIM21 in HL-1 atrial myocytes using a lentiviral vector. The expression of TRIM21 in the left atrium of the mouse MI model was significantly elevated. TRIM21 deficiency alleviated MI-induced atrial oxidative damage, Cx43 downregulation, atrial fibrosis and enlargement, and abnormalities in electrocardiogram parameters (prolongation of the P-wave and PR interval). TRIM21 overexpression in atrial myocyte HL-1 cells further enhanced oxidative damage and Cx43 downregulation, whereas these effects were reversed by the reactive oxygen species scavenger N-acetylcysteine. The findings suggest that TRIM21 likely induces Nox2 expression mechanistically by activating the NF-κB pathway, which in turn leads to myocardial oxidative damage, inflammation, and atrial remodeling.
Topics: Mice; Animals; Connexin 43; Atrial Fibrillation; Atrial Remodeling; Myocardial Infarction; Heart Atria; Oxidative Stress; Mice, Knockout; Inflammation
PubMed: 36996623
DOI: 10.1016/j.redox.2023.102679