scholarly journals Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Inseok Hwang ◽  
Je-Wook Park ◽  
Oh-Seok Kwon ◽  
Byounghyun Lim ◽  
Myunghee Hong ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Computational Modeling ◽  
Antiarrhythmic Drugs ◽  
Dominant Frequency ◽  
Dependent Manner ◽  
Ion Currents ◽  
Wild Type ◽  
Wave Dynamic ◽  
Phase Singularities ◽  
Dose Dependent

Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2+/−-deficient AF conditions by realistic in silico AF modeling.Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2+/− deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications.Results: We compared the wild-type and PITX2+/− deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2+/−-deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001), and PS number (p < 0.001) were more significant in PITX2+/−-deficient than wild-type AF. PITX2+/−-deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018).Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.

scholarly journals Computational modeling for antiarrhythmic drugs for atrial fibrillation according to the genotypes

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
I Hwang ◽  
J Park ◽  
O Kwon ◽  
B Lim ◽  
M Hong ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Computational Modeling ◽  
Antiarrhythmic Drugs ◽  
Science Research ◽  
Dominant Frequency ◽  
Dependent Manner ◽  
Wild Type ◽  
National Budget ◽  
In The Wild ◽  
Public Grant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant [HI19C0114] from the Ministry of Health and Welfare. Additionally, the work was funded by grants [NRF-2019R1C1C100907512], and [NRF-2020R1A2B01001695] from the Basic Science Research Program run by the National Research Foundation of Korea (NRF) under the Ministry of Science, ICT & Future Planning (MSIP). Background The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF) and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2+/- deficient AF conditions by realistic in-silico AF modeling. Methods We tested the V-AADs in AF modeling integrated with patients’ 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2+/- deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications. Results We compared the wild-type and PITX2+/- deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2+/- deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001) and PS number (p < 0.001) were more significant in PITX2+/- deficient than wild-type AF. PITX2+/- deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018). Conclusions The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamics and electrophysiological characteristics are different among the PITX2 deficient and the wild-type genotype models. BaselineChanges after AADClass ICClass IIIWild-typePITX2+/-p-valueWild-typePITX2+/-p-valueWild-typePITX2+/-p-valueWild-typePITX2+/-p-valueAPD90, (ms)243.7 ± 33.8184.4 ± 15.5<0.00138.2 ± 37.343.4 ± 56.20.223275.9 ± 43.5219.0 ± 39.2<0.001284.9 ± 32.8233.8 ± 71.4<0.001CV, (m/s)0.78 ± 0.320.70 ± 0.210.347-0.15 ± 0.18-0.20 ± 0.260.0330.63 ± 0.320.53 ± 0.300.0270.60 ± 0.360.43 ± 0.33<0.001Mean Smax0.787 ± 0.280.531 ± 0.18<0.0010.005 ± 0.260.115 ± 0.24<0.0010.828 ± 0.310.694 ± 0.320.0030.768 ± 0.320.608 ± 0.27<0.001Mean AFCL, (ms)146.96 ± 24.61164.78 ± 22.730.01122.62 ± 24.5537.92 ± 32.72<0.001165.44 ± 36.96190.85 ± 35.61<0.001169.05 ± 25.26203.35 ± 34.78<0.001Peak DF, (Hz)10.68 ± 2.9711.82 ± 3.340.211-2.98 ± 4.94-5.46 ± 4.66<0.00110.01 ± 4.397.23 ± 4.20<0.0016.30 ± 4.325.80 ± 4.070.301Mean DF, (Hz)6.80 ± 0.886.22 ± 0.710.012-1.95 ± 2.44-2.20 ± 1.990.2065.75 ± 1.784.53 ± 2.00<0.0014.14 ± 2.393.69 ± 2.000.077PS Number, (N)101086 ± 9608814150 ± 24778<0.001-59322 ± 99288-7409 ± 27856<0.00150579 ± 6523611568 ± 21868<0.00132951 ± 558643524 ± 8302<0.001PS Life Span, (ms)109.36 ± 113.90102.24 ± 226.640.889-24.87 ± 72.06-41.38 ± 126.350.073103.36 ± 180.6868.05 ± 162.790.14871.91 ± 141.8655.99 ± 217.970.454Table. Effects of AADs in the Wild-type and PITX2+/- Deficiency groupAbstract Figure. Wild-type vs. PITX2+/- baseline model

scholarly journals Spatial Changes in the Atrial Fibrillation Wave-Dynamics After Using Antiarrhythmic Drugs: A Computational Modeling Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Inseok Hwang ◽  
Je-Wook Park ◽  
Oh-Seok Kwon ◽  
Byounghyun Lim ◽  
Jisu Lee ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Computational Modeling ◽  
Coefficient Of Variation ◽  
Dominant Frequency ◽  
Dependent Manner ◽  
Spatial Change ◽  
Wave Dynamics ◽  
Spatial Changes ◽  
The Mean ◽  
Dose Dependent

Background: We previously reported that a computational modeling-guided antiarrhythmic drug (AAD) test was feasible for evaluating multiple AADs in patients with atrial fibrillation (AF). We explored the anti-AF mechanisms of AADs and spatial change in the AF wave-dynamics by a realistic computational model.Methods: We used realistic computational modeling of 25 AF patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal AF) reflecting the anatomy, histology, and electrophysiology of the left atrium (LA) to characterize the effects of five AADs (amiodarone, sotalol, dronedarone, flecainide, and propafenone). We evaluated the spatial change in the AF wave-dynamics by measuring the mean dominant frequency (DF) and its coefficient of variation [dominant frequency-coefficient of variation (DF-COV)] in 10 segments of the LA. The mean DF and DF-COV were compared according to the pulmonary vein (PV) vs. extra-PV, maximal slope of the restitution curves (Smax), and defragmentation of AF.Results: The mean DF decreased after the administration of AADs in the dose dependent manner (p < 0.001). Under AADs, the DF was significantly lower (p < 0.001) and COV-DF higher (p = 0.003) in the PV than extra-PV region. The mean DF was significantly lower at a high Smax (≥1.4) than a lower Smax condition under AADs. During the episodes of AF defragmentation, the mean DF was lower (p < 0.001), but the COV-DF was higher (p < 0.001) than that in those without defragmentation.Conclusions: The DF reduction with AADs is predominant in the PVs and during a high Smax condition and causes AF termination or defragmentation during a lower DF and spatially unstable (higher DF-COV) condition.

scholarly journals Clinical Outcomes of Computational Virtual Mapping-Guided Catheter Ablation in Patients With Persistent Atrial Fibrillation: A Multicenter Prospective Randomized Clinical Trial

2021 ◽  
Vol 8 ◽  
Author(s):  
Yong-Soo Baek ◽  
Oh-Seok Kwon ◽  
Byounghyun Lim ◽  
Song-Yi Yang ◽  
Je-Wook Park ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Trial ◽  
Catheter Ablation ◽  
Computational Modeling ◽  
Controlled Trial ◽  
Dominant Frequency ◽  
Complication Rates ◽  
Clinical Recurrence ◽  
Significant Difference

Background: Clinical recurrence after atrial fibrillation catheter ablation (AFCA) still remains high in patients with persistent AF (PeAF). We investigated whether an extra-pulmonary vein (PV) ablation targeting the dominant frequency (DF) extracted from electroanatomical map–integrated AF computational modeling improves the AFCA rhythm outcome in patients with PeAF.Methods: In this open-label, randomized, multi-center, controlled trial, 170 patients with PeAF were randomized at a 1:1 ratio to the computational modeling-guided virtual DF (V-DF) ablation and empirical PV isolation (E-PVI) groups. We generated a virtual dominant frequency (DF) map based on the atrial substrate map obtained during the clinical AF ablation procedure using computational modeling. This simulation was possible within the time of the PVI procedure. V-DF group underwent extra-PV V-DF ablation in addition to PVI, but DF information was not notified to the operators from the core lab in the E-PVI group.Results: After a mean follow-up period of 16.3 ± 5.3 months, the clinical recurrence rate was significantly lower in the V-DF than with E-PVI group (P = 0.018, log-rank). Recurrences appearing as atrial tachycardias (P = 0.145) and the cardioversion rates (P = 0.362) did not significantly differ between the groups. At the final follow-up, sinus rhythm was maintained without any AADs in 74.7% in the V-DF group and 48.2% in the E-PVI group (P < 0.001). No significant difference was found in the major complication rates (P = 0.489) or total procedure time (P = 0.513) between the groups. The V-DF ablation was independently associated with a reduced AF recurrence after AFCA [hazard ratio: 0.51 (95% confidence interval: 0.30–0.88); P = 0.016].Conclusions: The computational modeling-guided V-DF ablation improved the rhythm outcome of AFCA in patients with PeAF.Clinical Trial Registration: Clinical Research Information Service, CRIS identifier: KCT0003613.

scholarly journals Lipopolysaccharide biosynthesis-related genes are required for colony pigmentation of Porphyromonas gingivalis

Microbiology ◽  
2009 ◽  
Vol 155 (4) ◽  
pp. 1282-1293 ◽  
Author(s):  
Keiko Sato ◽  
Nobuo Kido ◽  
Yukitaka Murakami ◽  
Charles I. Hoover ◽  
Koji Nakayama ◽  
...  
Keyword(s):  
Cell Surface ◽  
Porphyromonas Gingivalis ◽  
Dependent Manner ◽  
Wild Type ◽  
Gene Encoding ◽  
Lipopolysaccharide Biosynthesis ◽  
Ladder Pattern ◽  
Surface Polysaccharides ◽  
Culture Supernatants ◽  
Dose Dependent

The periodontopathic bacterium Porphyromonas gingivalis forms pigmented colonies when incubated on blood agar plates as a result of accumulation of μ-oxo haem dimer on the cell surface. Gingipain–adhesin complexes are responsible for production of μ-oxo haem dimer from haemoglobin. Non-pigmented mutants (Tn6-5, Tn7-1, Tn7-3 and Tn10-4) were isolated from P. gingivalis by Tn4351 transposon mutagenesis [Hoover & Yoshimura (1994), FEMS Microbiol Lett 124, 43–48]. In this study, we found that the Tn6-5, Tn7-1 and Tn7-3 mutants carried Tn4351 DNA in a gene homologous to the ugdA gene encoding UDP-glucose 6-dehydrogenase, a gene encoding a putative group 1 family glycosyltransferase and a gene homologous to the rfa gene encoding ADP heptose-LPS heptosyltransferase, respectively. The Tn10-4 mutant carried Tn4351 DNA at the same position as that for Tn7-1. Gingipain activities associated with cells of the Tn7-3 mutant (rfa) were very weak, whereas gingipain activities were detected in the culture supernatants. Immunoblot and mass spectrometry analyses also revealed that gingipains, including their precursor forms, were present in the culture supernatants. A lipopolysaccharide (LPS) fraction of the rfa deletion mutant did not show the ladder pattern that was usually seen for the LPS of the wild-type P. gingivalis. A recombinant chimera gingipain was able to bind to an LPS fraction of the wild-type P. gingivalis in a dose-dependent manner. These results suggest that the rfa gene product is associated with biosynthesis of LPS and/or cell-surface polysaccharides that can function as an anchorage for gingipain–adhesin complexes.

Lidocaine and Mexiletine Inhibit Mitochondrial Oxidation in Rat Ventricular Myocytes

2001 ◽  
Vol 95 (3) ◽  
pp. 766-770 ◽  
Author(s):  
Yasuo Tsutsumi ◽  
Shuzo Oshita ◽  
Takashi Kawano ◽  
Hiroshi Kitahata ◽  
Yoshinobu Tomiyama ◽  
...  
Keyword(s):  
Antiarrhythmic Drugs ◽  
Ventricular Myocytes ◽  
Atp Synthesis ◽  
Dependent Manner ◽  
Mitochondrial Potential ◽  
Rat Ventricular Myocytes ◽  
Mitochondrial Redox State ◽  
Male Wistar Rats ◽  
Mitochondrial Oxidation ◽  
Dose Dependent

Background Accumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate-sensitive K+ (K(ATP)) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial K(ATP) channel activities. Methods Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 microM), a selective mitochondrial K(ATP) channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, a protonophore that uncouples respiration from ATP synthesis and collapses the mitochondrial potential. Results Diazoxide-induced oxidation of flavoproteins and the redox changes were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial K(ATP) channel blocker, suggesting that flavoprotein fluorescence can be used as an index of mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Lidocaine (10(-3) to 10 mM) and mexiletine (10(-3) to 10 mM) reduced oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98+/-63 microM for lidocaine and 107+/-89 microM for mexiletine. Conclusions Both lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial K(ATP) channels.

scholarly journals Choline Induces Transcriptional Repression and Proteasomal Degradation of the Malarial Phosphoethanolamine Methyltransferase

2007 ◽  
Vol 6 (9) ◽  
pp. 1618-1624 ◽  
Author(s):  
William Harold Witola ◽  
Choukri Ben Mamoun
Keyword(s):  
Transcriptional Repression ◽  
Morphological Changes ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Wild Type ◽  
Active Synthesis ◽  
Rapid Multiplication ◽  
Gene And Protein Expression ◽  
Transgenic Parasites ◽  
Dose Dependent

ABSTRACT During its intraerythrocytic life cycle, the malaria parasite Plasmodium falciparum undergoes dramatic metabolic and morphological changes and multiplies to produce up to 36 new daughter parasites. This rapid multiplication of the parasite requires an active synthesis of new membranes. The major component of these membranes, phosphatidylcholine, is synthesized via two metabolic routes, the CDP-choline pathway, which uses host choline as a precursor, and the plant-like serine decarboxylase-phosphoethanolamine methyltransferase (SDPM) pathway, which uses host serine as a precursor. Here we provide evidence indicating that the activity of the SDPM pathway is regulated by the CDP-choline precursor, choline. We show that the phosphoethanolamine methyltransferase, Pfpmt, a critical enzyme in the SDPM pathway, is down-regulated at the transcriptional level as well as targeted for degradation by the proteasome in the presence of choline. Transcript analysis revealed that PfPMT transcription is repressed by choline in a dose-dependent manner. Immunoblotting, pulse-chase experiments, and immunoprecipitation studies demonstrated that Pfpmt degradation occurs not only in wild-type but also in transgenic parasites constitutively expressing Pfpmt. The proteasome inhibitor bortezomib inhibited choline-mediated Pfpmt degradation. These data provide the first evidence for metabolite-mediated transcriptional and proteasomal regulation in Plasmodium and will set the stage for the use of this system for conditional gene and protein expression in this organism.

scholarly journals Genetic or Enzymatic Disruption of Aromatase Inhibits the Growth of Ectopic Uterine Tissue

2002 ◽  
Vol 87 (7) ◽  
pp. 3460-3466 ◽  
Author(s):  
Zongjuan Fang ◽  
Sijun Yang ◽  
Bilgin Gurates ◽  
Mitsutoshi Tamura ◽  
Evan Simpson ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Mouse Model ◽  
Lesion Size ◽  
Dependent Manner ◽  
Wild Type ◽  
Uterine Tissue ◽  
Abdominal Organs ◽  
Letrozole Treatment ◽  
Key Enzyme ◽  
Dose Dependent

Aromatase P450 (P450arom) is the key enzyme for the biosynthesis of estrogen that is essential for the growth of human endometriosis, a pathology characterized by endometrium-like tissue on the peritoneal surfaces of abdominal organs manifest by pelvic pain and infertility. Surgically transplanted autologous uterine tissue to ectopic sites on the peritoneum in mice has been used as an animal model to study endometriosis. Using this mouse model, we evaluated the roles of the P450arom gene and aromatase enzyme activity in the growth of endometriosis represented by ectopic uterine tissues in mice. Endometriosis was induced surgically in the following groups of mice: 1) untreated transgenic mice with disrupted P450arom gene (ArKO); 2) ArKO mice treated with systemic estrogen; 3) untreated wild-type (WT) mice; 4) WT mice treated with estrogen; 5) WT mice treated with the aromatase inhibitor, letrozole; and 6) WT mice treated with letrozole and estrogen. Each group contained eight mice; +/+ littermates of ArKO mice were used as WT controls. Treatment with estrogen increased the size of ectopic uterine tissues in ArKO and WT mice significantly. The ectopic uterine lesions in untreated and estrogen-treated ArKO mice were strikingly smaller than those in untreated and estrogen-treated WT controls, respectively. Systemic treatment of WT mice with letrozole significantly decreased the lesion size in a dose-dependent manner. The addition of estrogen to letrozole treatment increased the ectopic lesion size, although these lesions were significantly smaller than those in mice treated with estrogen only. As tissue controls, the effects of these conditions on normally located (eutopic) uterine tissue were evaluated. The effects of disruption of the P450arom gene and treatments with letrozole and estrogen seemed to be more profound on ectopic tissues, suggesting that ectopic tissues might be more sensitive to estrogen for growth. We conclude that both an intact P450arom gene and the presence of aromatase enzyme activity are essential for the growth of ectopic uterine tissue in a mouse model of endometriosis.

Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1456-1463 ◽  
Author(s):  
Karen L. Jones ◽  
Sascha C. Hughan ◽  
Sacha M. Dopheide ◽  
Richard W. Farndale ◽  
Shaun P. Jackson ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Collagen Matrix ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Wild Type ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1 ◽  
Dose Dependent ◽  
Deficient Mice ◽  
Endothelial Cell Adhesion

The functional importance of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in platelets is unclear. Because PECAM-1 represents a newly assigned immunoglobulin–ITIM superfamily member expressed on the surface of platelets, it was hypothesized that it may play an important regulatory role in modulating ITAM-bearing receptors such as collagen (GP)VI receptor and FcγRIIA. To examine the functional role of PECAM-1 in regulating platelet-collagen interactions, 2 different approaches were applied using recombinant human PECAM-1–immunoglobulin chimeras and platelets derived from PECAM-1–deficient mice. Stimulation of platelets by collagen-, (GP)VI-selective agonist, collagen-related peptide (CRP)–, and PECAM-1–immunoglobulin chimera induced tyrosine phosphorylation of PECAM-1 in a time- and dose-dependent manner. Activation of PECAM-1 directly through the addition of soluble wild-type PECAM-1–immunoglobulin chimera, but not mutant K89A PECAM-1–immunoglobulin chimera that prevents homophilic binding, was found to inhibit collagen- and CRP-induced platelet aggregation. PECAM-1–deficient platelets displayed enhanced platelet aggregation and secretion responses on stimulation with collagen and CRP, though the response to thrombin was unaffected. Under conditions of flow, human platelet thrombus formation on a collagen matrix was reduced in a dose-dependent manner by human PECAM-1–immunoglobulin chimera. Platelets derived from PECAM-1–deficient mice form larger thrombi when perfused over a collagen matrix under flow at a shear rate of 1800 seconds−1 compared to wild-type mice. Collectively, these results indicate that PECAM-1 serves as a physiological negative regulator of platelet-collagen interactions that may function to negatively limit growth of platelet thrombi on collagen surfaces.

scholarly journals Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice

Hypertension ◽  
2020 ◽  
Vol 76 (2) ◽  
pp. 381-392 ◽  
Author(s):  
Yun-Long Zhang ◽  
Hua-Jun Cao ◽  
Xiao Han ◽  
Fei Teng ◽  
Chen Chen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Bone Marrow ◽  
Chemokine Receptor ◽  
Knockout Mice ◽  
Bone Marrow Cells ◽  
Atrial Remodeling ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Chemokine Ligands

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2 + immune cells markedly increased in Ang II–infused atria in a time-dependent manner. Moreover, Ang II–infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2 + monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.

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