Background and Purpose Inhibition of the G‐protein gated ACh‐activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti‐arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF‐1407 (3‐methyl‐1‐[5‐phenyl‐4‐[4‐(2‐pyrrolidin‐1‐ylethoxymethyl)‐1‐piperidyl]thieno[2,3‐d]pyrimidin‐6‐yl]azetidin‐3‐ol), were characterised for the first time in vitro and investigated in horses with persistent AF. Experimental Approach The pharmacological ion channel profile of XAF‐1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self‐sustained AF. The electrophysiological effects of XAF‐1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug‐induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction. Key Results XAF‐1407 potently and selectively inhibited Kir3.1/3.4 and Kir3.4/3.4, underlying the IK,ACh current. XAF‐1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF‐1407 shortened atrioventricular‐nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia. Conclusion and Implications XAF‐1407 efficiently cardioverted sustained tachypacing‐induced AF of short duration in horses without notable side effects. This supports IK,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.

Rationale: Athletes present with atrioventricular node (AV node) dysfunction manifesting as AV block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: AV block in athletes is attributed to high vagal tone. Here we investigated the alternative hypothesis that electrical remodeling of the AV node is responsible. Methods and Results: Radio-telemetry ECG data and AV node biopsies were collected in sedentary and trained Standardbred racehorses, a large-animal model of the athlete's heart. Trained horses presented with longer PR intervals (that persisted under complete autonomic block) versus sedentary horses, concomitant with reduced expression of key ion channels involved in AV node conduction: L-type Ca2+ channel subunit CaV1.2 and the hyperpolarization-activated cyclic nucleotide gated channel 4 (HCN4). AV node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length and AV node refractory period was observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected AV node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of CaV1.2 and HCN4. Correspondingly, patch clamp recordings in isolated AV node myocytes demonstrated a training-induced reduction in ICa,L and If density that likely contributed to the observed lower frequency of action potential firing in trained cohorts. microRNA (miR) profiling and in vitro studies revealed miR-211-5p and miR-432 as direct regulators of CaV1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced AV node dysfunction is underscored by likely miR-mediated transcriptional remodeling that translates into reduced current density of key ionic currents involved in impulse generation and conduction. We conclude that electrical remodeling is a key mechanism underlying AV block in athletes.

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Background: Long-term exercise induces cardiac remodeling that potentially influences the electrical properties of the heart. Hypothesis/objectives: We assessed whether training alters cardiac conduction in Standardbred racehorses. Animals: Two hundred one trained and 52 untrained Standardbred horses. Methods: Cross-sectional study. Resting ECG recordings were analyzed to assess heart rate (HR) along with standard ECG parameters and for identification of atrial and ventricular arrhythmias. An electrophysiological study was performed in 13 horses assessing the effect of training on sinoatrial (SA) and atrioventricular (AV) nodal function by sinus node recovery time (SNRT) and His signal recordings. Age and sex adjustments were implemented in multiple and logistic regression models for comparison.Results: Resting HR in beats per minute (bpm) was lower in trained vs untrained horses (mean, 30.8 ± 2.6 bpm vs 32.9 ± 4.2 bpm; P = .001). Trained horses more often displayed second-degree atrioventricular block (2AVB; odds ratio, 2.59; P = .04). No difference in SNRT was found between groups (n = 13). Mean P-A, A-H, and H-V intervals were 71 ± 20, 209 ± 41, and 134 ± 41 ms, respectively (n = 7). We did not detect a training effect on AV-nodal conduction intervals. His signals were present in 1 horse during 2AVB with varying H-V interval preceding a blocked beat. Conclusions and Clinical Importance:We identified decreased HR and increased frequency of 2AVB in trained horses. In 5 of 7 horses, His signal recordings had variable H-V intervals within each individual horse, providing novel insight into AV conduction in horses.

Highlights Persistent atrial fibrillation is associated with increased fibroblast accumulation. Six weeks of persistent AF is not associated with structural remodeling. Fibroblasts are potentially contributing to alteration in atrial electrophysiology.