Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNFα, in exercised-induced atrial remodelling. Accordingly, exercise induces TNFα-dependent activation of both NFκB and p38MAPK, while TNFα inhibition (with etanercept), TNFα gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNFα as a key factor in the pathology of intense exercise-induced AF.

The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43. However, it is unknown whether other factors contribute to the conduction defects observed in Irx3 knockout (Irx3−/−) mice. In this study, we show that during the early postnatal period, Irx3−/− mice develop morphological defects in the VCS which are temporally dissociated from changes in gap junction expression. These morphological defects were accompanied with progressive changes in the cardiac electrocardiogram including right bundle branch block. Hypoplastic VCS was not associated with increased apoptosis of VCS cardiomyocytes but with a lack of recruitment and maturation of ventricular cardiomyocytes into the VCS. Computational analysis followed by functional verification revealed that Irx3 promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx5. Altogether, these results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx3 is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx5 and Nkx2.5.

The fast transient outward potassium current (I to,f ) plays a critical role in the electrical and contractile properties of the myocardium. I to,f channels are formed by the co-assembly of the pore-forming ␣-subunits, Kv4.2 and Kv4.3, together with the accessory ␤-subunit KChIP2. Reductions of I to,f are common in the diseased heart, which is also associated with enhanced stimulation of ␤-adrenergic receptors (␤-ARs). We used cultured neonatal rat ventricular myocytes to examine how chronic ␤-AR stimulation decreases I to,f . To determine which downstream pathways mediate these I to,f changes, adenoviral infections were used to inhibit CaMKII␦c, CaMKII␦b, calcineurin, or nuclear factor B (NF-B). We observed that chronic ␤-AR stimulation with isoproterenol (ISO) for 48 h reduced I to,f along with mRNA expression of all three of its subunits (Kv4.2, Kv4.3, and KChIP2). Inhibiting either CaMKII␦c nor CaMKII␦b did not prevent the ISO-mediated I to,f reductions, even though CaMKII␦c and CaMKII␦b clearly regulated I to,f and the mRNA expression of its subunits. Likewise, calcineurin inhibition did not prevent the I to,f reductions induced by ␤-AR stimulation despite strongly modulating I to,f and subunit mRNA expression. In contrast, NF-B inhibition partly rescued the ISO-mediated I to,f reductions in association with restoration of KChIP2 mRNA expression. Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as ␤-AR stimulation. In conclusion, NF-B, and not CaMKII␦ or calcineurin, partly mediates the I to,f reductions induced by chronic ␤-AR stimulation. Both mRNA and KChIP2 promoter data suggest that the ISO-induced I to,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-B activation.Fast cardiac transient outward potassium currents are generated by channels comprised of voltage-gated ␣-pore-forming subunits (which in humans/canines is predominantly Kv4.3, and in rodents is Kv4.2 and Kv4.3) and the accessory ␤-subunit KChIP2 (1). These currents play a critical role in early cardiac repolarization (1), excitation contraction-coupling (2, 3), and arrhythmias (4). I to,f and its molecular constituents are invariably reduced in cardiac hypertrophy and disease (1), and heart disease is also characterized by elevations in catecholamines and consequently enhanced activation of ␤-adrenergic receptors (␤-AR) 6 (5). Although chronic ␤-AR stimulation has been shown to decrease I to,f (6), the molecular mechanisms underlying regulation of I to,f by ␤-ARs remain unclear.I to,f is regulated by several pathways activated in the diseased myocardium, such as calcineurin, nuclear factor-activated T-cells (NFAT) (6, 7) and mitogen activated protein kinases (8). Although calcineurin/NFAT signaling regulates I to,f in a manner that is model dependent (6, 9, 10), this pathway does not mediate ␣-AR-induced changes in I to,f or its molecular subunits (9,10). We previously showed that ␣-AR stimulation activates the transcription factor nuclear factor B (NF-B), which media...

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