Background: Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap‐junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine‐mediated changes in connexin expression. Methods and Results: Fifty‐four patients with different inflammatory diseases and elevated C‐reactive protein were prospectively enrolled, and electrocardiographic P‐wave dispersion indices, cytokine levels (interleukin‐6, tumor necrosis factor‐α, interleukin‐1, interleukin‐10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C‐reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin‐6 on connexin expression were studied in HL‐1 mouse atrial myocytes. In patients with active inflammatory diseases, P‐wave dispersion indices were increased but rapidly decreased within days when C‐reactive protein normalizes and interleukin‐6 levels decline. In inflammatory disease patients, both P‐wave dispersion indices and interleukin‐6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin‐6 significantly reduced connexin expression in HL‐1 cells. Conclusions: Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin‐6 elevation, rapidly induces atrial electrical remodeling by down‐regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.

Background: The optimal timing to administer non–vitamin K oral anticoagulants ( NOAC s) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOAC s for secondary prevention. Methods and Results: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA ₂ DS ₂ ‐ VAS c score >4 and less reduced renal function. Thirty‐two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOAC s within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke. Conclusions: In patients with acute ischemic stroke and atrial fibrillation, treatment with NOAC s was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Objective: Patients with rheumatoid arthritis (RA) are twice as likely to experience sudden cardiac death compared with individuals without RA. Although the underlying mechanisms of this have not been clarified, evidence points to the effects of systemic inflammation on ventricular repolarization. Accordingly, prolongation of the corrected QT (QTc) interval is more frequent in patients with RA compared with individuals without RA also correlating with C‐reactive protein (CRP) and predicting all‐cause mortality. Tocilizumab (TCZ) is an anti–interleukin‐6 receptor antibody that potently inhibits inflammatory activation in RA, with rapid normalization of acute‐phase reactant levels, including the CRP level. Therefore, we hypothesized that TCZ may normalize the QTc interval by dampening systemic inflammation, thus reducing the risk of arrhythmia in patients with RA.Methods: Seventeen consecutive patients with active RA who were scheduled to receive TCZ once every 4 weeks underwent a clinical examination, electrocardiography, and blood sampling just before the first injection with TCZ and again after 3 months and 6 months of treatment.Results: At baseline, 76% of patients displayed prolongation of the QTc interval (mean ± SD 452.3 ± 35.8 msec). TCZ treatment was associated with a rapid and significant reduction of the QTc interval to mean values <440 msec (up to 428.1 ± 34.3 msec). Throughout the study, QTc interval shortening correlated with decreases in both the CRP level, and more strongly, with circulating tumor necrosis factor α level.Conclusion: These data provide further evidence of the close link between the degree of systemic inflammation and QTc interval duration in RA and also suggest an anti‐arrhythmic potential for TCZ treatment, which may have a beneficial impact on the mortality of these patients.

Background and Purpose—: Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non–vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods—: Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results—: Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95–5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63–9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83–3.16), and CHA ₂ DS ₂ -VASc score (OR, 1.72 for each point increase; 95% CI, 1.58–1.88) were associated with ischemic events. Among the CHA ₂ DS ₂ -VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33–0.61). Conclusions—: In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA ₂ DS ₂ -VASc score were associated with increased risk of cerebrovascular events.

Background: In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results: HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3–8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0–6.0) of those without HT ; 53.1% of patients with HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24–2.35). Conclusions: In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability.

Objective: Newborns of mothers positive for anti‐Ro/SSA autoantibodies may develop a series of electrocardiographic (EKG) disturbances. Prolongation of the corrected QT (QTc) interval was recently reported in a significant proportion of children with maternally acquired anti‐Ro/SSA antibodies, with a concomitant disappearance of EKG abnormalities and acquired maternal autoantibodies during the first year, suggesting a direct, reversible electrophysiologic effect of anti‐Ro/SSA antibodies on the ventricular repolarization. On this basis, we investigated whether these antibodies may also affect cardiac repolarization in anti‐Ro/SSA–positive adult patients with connective tissue diseases.Methods: Fifty‐seven patients with connective tissue diseases were selected: 31 had anti‐Ro/SSA antibodies and 26 did not (controls). In all subjects, we analyzed the QTc interval, heart rate variability, and signal‐averaged high‐resolution EKG recording.Results: Anti‐Ro/SSA–positive patients showed a significant prolongation of the mean QTc interval compared with the controls (mean ± SD 445 ± 21 versus 419 ± 17 msec; P = 0.000005). Eighteen of the 31 anti‐Ro/SSA–positive patients (58%) and none of the 26 anti‐Ro/SSA–negative patients had QTc values above the upper limit of normal (440 msec). Both groups had a reduction in heart rate variability, with a prevalence for the sympathetic nervous system and a high incidence of ventricular late potentials; these values were not significantly different between the 2 groups.Conclusion: Adult patients with anti‐Ro/SSA–positive connective tissue diseases showed a high prevalence of QTc interval prolongation. This feature, with the concomitant abnormalities in the autonomic tone and ventricular late excitability observed in all patients studied, suggests that anti‐Ro/SSA–positive patients may have a particularly high risk of developing life‐threatening arrhythmias.