Mechanisms of pulmonary arterial hypertension-induced atrial fibrillation: insights from multi-scale models of the human atria.

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10-2 µM in the RA versus 0.9 × 10-3 µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: -0.5 m s-1 in the RA versus -0.05 m s-1 in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Mechanistic insight into the functional role of human sinoatrial node conduction pathways and pacemaker compartments heterogeneity: A computer model analysis.

The sinoatrial node (SAN), the primary pacemaker of the heart, is responsible for the initiation and robust regulation of sinus rhythm. 3D mapping studies of the ex-vivo human heart suggested that the robust regulation of sinus rhythm relies on specialized fibrotically-insulated pacemaker compartments (head, center and tail) with heterogeneous expressions of key ion channels and receptors. They also revealed up to five sinoatrial conduction pathways (SACPs), which electrically connect the SAN with neighboring right atrium (RA). To elucidate the role of these structural-molecular factors in the functional robustness of human SAN, we developed comprehensive biophysical computer models of the SAN based on 3D structural, functional and molecular mapping of ex-vivo human hearts. Our key finding is that the electrical insulation of the SAN except SACPs, the heterogeneous expression of If, INa currents and adenosine A1 receptors (A1R) across SAN pacemaker-conduction compartments are required to experimentally reproduce observed SAN activation patterns and important phenomena such as shifts of the leading pacemaker and preferential SACP. In particular, we found that the insulating border between the SAN and RA, is required for robust SAN function and protection from SAN arrest during adenosine challenge. The heterogeneity in the expression of A1R within the human SAN compartments underlies the direction of pacemaker shift and preferential SACPs in the presence of adenosine. Alterations of INa current and fibrotic remodelling in SACPs can significantly modulate SAN conduction and shift the preferential SACP/exit from SAN. Finally, we show that disease-induced fibrotic remodeling, INa suppression or increased adenosine make the human SAN vulnerable to pacing-induced exit blocks and reentrant arrhythmia. In summary, our computer model recapitulates the structural and functional features of the human SAN and can be a valuable tool for investigating mechanisms of SAN automaticity and conduction as well as SAN arrhythmia mechanisms under different pathophysiological conditions.

Chamber-specific wall thickness features in human atrial fibrillation.

Persistent atrial fibrillation (AF) is not effectively treated due to a lack of adequate tools for identifying patient-specific AF substrates. Recent studies revealed that in 30-50% of patients, persistent AF is maintained by localized drivers not only in the left atrium (LA) but also in the right atrium (RA). The chamber-specific atrial wall thickness (AWT) features underlying AF remain elusive, though the important role of AWT in AF is widely acknowledged. We aimed to provide direct evidence of the existence of distinguished RA and LA AWT features underlying AF drivers by analysing functionally and structurally mapped human hearts ex vivo. Coronary-perfused intact human atria (n = 7, 47 ± 14 y.o.; two female) were mapped using panoramic near-infrared optical mapping during pacing-induced AF. Then the hearts were imaged at approximately 170 µm3 resolution by 9.4 T gadolinium-enhanced MRI. The heart was segmented, and 3D AWT throughout atrial chambers was estimated and analysed. Optical mapping identified six localized RA re-entrant drivers in four hearts and four LA drivers in three hearts. All RA AF drivers were anchored to the pectinate muscle junctions with the crista terminalis or atrial walls. The four LA AF drivers were in the posterior LA. RA (n = 4) with AF drivers were thicker with greater AWT variation than RA (n = 3) without drivers (5.4 ± 2.6 mm versus 5.0 ± 2.4 mm, T-test p < 0.05; F-test p < 0.05). Furthermore, AWT in RA driver regions was thicker and varied more than in RA non-driver regions (5.1 ± 2.5 mm versus 4.4 ± 2.2 mm, T-test p < 0.05; F-test p < 0.05). On the other hand, LA (n = 3) with drivers was thinner than the LA (n = 4) without drivers. In particular, LA driver regions were thinner than the rest of LA regions (3.4 ± 1.0 mm versus 4.2 ± 1.0 mm, T-test p < 0.05). This study demonstrates chamber-specific AWT features of AF drivers. In RA, driver regions are thicker and have more variable AWT than non-driver regions. By contrast, LA drivers are thinner than non-drivers. Robust evaluation of patient-specific AWT features should be considered for chamber-specific targeted ablation.