Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.

P3748Reproducibility of magnetocardiographic imaging of atrial electrophysiology in patients with paroxysmal atrial fibrillation and healthy subjects

Since tangential currents are better detectable as magnetic than electric signals at the body surface, magnetocardiographic mapping (MCG) can be more sensitive than ECG to atrial electrophysiologic alteration, such as abnormal interatrial conduction and/or dispersion of atrial repolarization, as mechanisms underlying the occurrence of paroxysmal atrial fibrillation (PAF). We had previously reported that visual analysis of the magnetic field distribution (MFD) dynamics may evidence an inversion of atrial MFD early during the P-wave suggesting atrial repolarization overlapping depolarization along the descending limb of the P-wave (Guida et al 2018). Aim of this study was to systematically evaluate the reproducibility of such observation and to evaluate the reliability of non-invasive MCG imaging of atrial electrophysiology carried out in our unshielded hospital laboratory. Methods MCG was recorded, in sinus rhythm (SR), with an unshielded 36-channel SQUID-system providing about 30–40 fT/√Hz sensitivity in bandwidth DC-250Hz (sampling frequency 1kHz). MCG data of 40 patients with PAF (PAFp) and 40 age-matched healthy controls (HC), with at least two subsequent recordings to evaluate reproducibility and optimal S/N ratio, were retrospectively analyzed. The dynamics of atrial MFD was studied, at 1 ms time resolution, to identify the onset of atrial repolarization (AR), in respect of the P-wave and PR interval duration. To localize atrial sources, the inverse solution was calculated with the Effective Magnetic Dipole (EMD) model, also after subtraction of the atrial repolarization. MCG parameters of atrial electromagnetic vector (EMV) were also calculated. The reproducibility was evaluated with the intraclass correlation coefficient (ICC). Results High resolution analysis of atrial MFD dynamics confirmed that atrial repolarization field overlaps atrial depolarization during the last third of the P-wave in most investigated subjects. Thus, subtraction of average AR MFD is necessary to discover and image the left atrial depolarization pathway. The reproducibility of MCG estimate of atrial MFD and of EMV parameters was good (average ICC >0.7). In PAFp, MCG evidenced abnormality of AR MFD consistent with dispersion of atrial repolarization (Figure 1), as previously reported with simultaneous MCG and MAP recordings (Fenici & Brisinda, 2007); however, such evaluation is reliable only with optimal S/N ratio during the PR interval. Conclusions Unshielded MCG in SR is sensitive enough to non-invasively image atrial electrophysiology. Visual analysis of atrial MFD dynamics with high temporal resolution reproductively confirmed that AR MFD initiates early, within the descending limb of the P-wave, masking the deeper magnetic field generated by left atrial depolarization currents. MCG can image abnormality of AR MFD in PAFp, suggestive of dispersion of atrial action potential duration. Quantitative estimate of atrial EMV parameters differentiates PAFp from HC.

Genetic ablation or pharmacological inhibition of Kv1.1 potassium channel subunits impairs atrial repolarization in mice

Voltage-gated Kv1.1 potassium channel α-subunits, encoded by the Kcna1 gene, have traditionally been regarded as neural-specific with no expression or function in the heart. However, recent data revealed that Kv1.1 subunits are expressed in atria where they may have an overlooked role in controlling repolarization and arrhythmia susceptibility independent of the nervous system. To explore this concept in more detail and to identify functional and molecular effects of Kv1.1 channel impairment in the heart, atrial cardiomyocyte patch-clamp electrophysiology and gene expression analyses were performed using Kcna1 knockout ( Kcna1−/−) mice. Specifically, we hypothesized that Kv1.1 subunits contribute to outward repolarizing K+ currents in mouse atria and that their absence prolongs cardiac action potentials. In voltage-clamp experiments, dendrotoxin-K (DTX-K), a Kv1.1-specific inhibitor, significantly reduced peak outward K+ currents in wild-type (WT) atrial cells but not Kcna1−/− cells, demonstrating an important contribution by Kv1.1-containing channels to mouse atrial repolarizing currents. In current-clamp recordings, Kcna1−/− atrial myocytes exhibited significant action potential prolongation which was exacerbated in right atria, effects that were partially recapitulated in WT cells by application of DTX-K. Quantitative RT-PCR measurements showed mRNA expression remodeling in Kcna1−/− atria for several ion channel genes that contribute to the atrial action potential including the Kcna5, Kcnh2, and Kcnj2 potassium channel genes and the Scn5a sodium channel gene. This study demonstrates a previously undescribed heart-intrinsic role for Kv1.1 subunits in mediating atrial repolarization, thereby adding a new member to the already diverse collection of known K+ channels in the heart.