Background: Ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide channel to reduce pacing current with a possible increasing risk of atrial fibrillation (AF). Objective: To determine the effects of IVA on atrial action potentials, atrial arrhythmic activities and intracellular calcium homeostasis. Methods: Langendorff-perfused hearts and atrial myocytes from New Zealand White rabbits were used to record 12-lead ECGs，left atrial monophasic APs and Ca2+ sparks. Ca2+ handing related protein from left atrium were tested using western blotting. Results: IVA (0.1-10 μM) slowed the HR and prolonged the atrial MAPD90 (n=8, p<0.05) and induced atrial arrhythmias in 26% and 77% of hearts paced at cycle lengths of 350 ms and 570 ms, respectively (n=23 and 13, p<0.05). In hearts treated with either 0.3 µM acetylcholine (ACh) or 2 nM ATX-II with modulated atrial MAPDs, IVA (0.1-10 µM) caused either shortening or prolongation of MAPD90, respectively (n=18 and 21, p<0.05) and atrial arrhythmias in 61.9% and 44.4% of hearts (p<0.05). IVA induced delayed afterdepolarizations in 41.7%, 62.5% and 50% of cells in the absence and presence of either ATX-II or ACh, respectively (n=12, 8 and 8, p<0.05). IVA (0.03-3 μM) increased the frequency, amplitude and full width at half-maximum (n=22, p<0.05), and the expression of ryanodine receptor and Na+/Ca2+ exchanger with decreased sarcoplasmic reticulum calcium pump (n=4-5, p<0.05). Conclusion: IVA caused a blunted HR reduction and increased atrial proarrhythmic risk in hearts with slow rate, enhanced vagal tone and late INa, and DADs resulting from enhanced Ca2+ release.

Aims: To assess the effect of oral anticoagulant (OAC) administration on incidence of dementia in patients with atrial fibrillation (AF) with Systematic review and meta-analysis in according with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. Methods: We systematically searched the electronic databases including Pubmed, Embase, Cochrane library, and ClinicalTrails.gov for relevant articles. The primary outcome was the incidence of dementia. The adjusted risk ratio (RR), odds ratio, or hazard ratio were extracted and pooled by the random-effects models. Subgroup analysis was performed according to the setting observational window. Risk of bias was assessed using the Newcastle-Ottawa Scale, while publication bias was assessed by the Begg’s and Egger’s tests. Results: Nine studies included in this review (2 prospective and 7 retrospective observational studies, including 613,920 patients). The results presented the significant association between OAC therapy and the reduced risk of dementia compared with no treatment (RR [95%CI] =0.72 [0.60, 0.86], I2=97.2%; P =0.000). In the subgroup analysis, the pooled RR became statistically non-significant (including four studies, RR [95%CI] =0.75 [0.51, 1.10], I2=98.8%; P =0.000). There is no significant risk of bias and publication bias. Conclusions: This study indicated the protective effect of OAC therapy for dementia in patients with AF. However, the results are limited because of high heterogeneity, inconsistent direction of effect in subgroup analysis. Further prospective well-designed study is needed with longer follow-up duration in younger patients.

Background and Purpose: We investigate mechanisms for potential pro-arrhythmic effects of hydroxychloroquine (HCQ) alone, or combined with azithromycin (AZM), in Covid-19 management supplementing the limited available experimental cardiac safety data. Experimental Approach: We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay Schema IC50 paradigms, molecular modelling, cardiac multi-electrode array and voltage (RH237) mapping, ECG studies, and Ca2+ (Rhod-2 AM) mapping in isolated Langendorff-perfused guinea-pig hearts with human in-silico ion current modelling. Key Results: HCQ blocked IKr and IK1 with IC50s (10±0.6 and 34±5.0 µM) within clinical therapeutic ranges, INa and ICaL at higher IC50s, leaving Ito and IKs unaffected. AZM produced minor inhibition of INa, ICaL, IKs, and IKr,, sparing IK1 and Ito. HCQ+AZM combined inhibited IKr and IK1 with IC50s of 7.7±0.8 µM and 30.4±3.0 µM, sparing INa, ICaL and Ito. Molecular modelling confirmed potential HCQ binding to hERG. HCQ slowed heart rate and ventricular conduction. It prolonged PR, QRS and QT intervals, and caused prolonged, more heterogeneous, action potential durations and intracellular Ca2+ transients. These effects were accentuated with combined HCQ+AZM treatment, which then elicited electrical alternans, re-entrant circuits and wave break. Modelling studies attributed these to integrated HCQ and AZM actions reducing IKr and IK1, thence altering cell Ca2+ homeostasis. Conclusion and implications: Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting IKr, IKs with resulting effects on cellular Ca2+ signalling, and action potential propagation and duration. These findings provide an electrophysiological basis for recent FDA cardiac safety guidelines cautioning against combining HCQ/AZM when treating Covid-19.