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

Abstract

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.

Electrifying insights into cardiac arrhythmias: from molecular mechanisms to therapeutic translations

“…The studies presented in this special edition of Interface Focus represent a broad spectrum of approaches that add to our body of arrhythmic knowledge and understanding. They include in vivo [1,2], in silico [3][4][5][6][7], in vitro [8] and ex vivo [7,9] studies covering animal [1,7,9] and human [3,8] models and clinical imaging [2]. Most consider implications for the atria [1,2,[4][5][6], reflecting the dominant morbidity and mortality burden of atrial fibrillation in many parts of the world, with the balance studying ventricular electrical function [3,7,9].…”

“…They include in vivo [1,2], in silico [3][4][5][6][7], in vitro [8] and ex vivo [7,9] studies covering animal [1,7,9] and human [3,8] models and clinical imaging [2]. Most consider implications for the atria [1,2,[4][5][6], reflecting the dominant morbidity and mortality burden of atrial fibrillation in many parts of the world, with the balance studying ventricular electrical function [3,7,9]. The motivating pro-arrhythmic disease states are similarly varied and include metabolic syndrome [1], atrial fibrillation [2,4,6,8], long-QT syndrome [3], pulmonary arterial hypertension [5] and myocardial induced heart failure [9].…”

“…Most consider implications for the atria [1,2,[4][5][6], reflecting the dominant morbidity and mortality burden of atrial fibrillation in many parts of the world, with the balance studying ventricular electrical function [3,7,9]. The motivating pro-arrhythmic disease states are similarly varied and include metabolic syndrome [1], atrial fibrillation [2,4,6,8], long-QT syndrome [3], pulmonary arterial hypertension [5] and myocardial induced heart failure [9]. While some of the studies explicitly consider a range of scales or dimensions [3,5,6], others focus on the cellular or subcellular space [7,9], the whole heart [2,4,8] or non-invasive torso-scale signals [1].…”

“…The motivating pro-arrhythmic disease states are similarly varied and include metabolic syndrome [1], atrial fibrillation [2,4,6,8], long-QT syndrome [3], pulmonary arterial hypertension [5] and myocardial induced heart failure [9]. While some of the studies explicitly consider a range of scales or dimensions [3,5,6], others focus on the cellular or subcellular space [7,9], the whole heart [2,4,8] or non-invasive torso-scale signals [1].…”

“…Together, the studies reported in this special edition of Interface Focus are a taster of the exciting research tracks currently pursued in the cardiac arrhythmia field. Some of these works are poised for clinical and health science translation [1,2], others present tantalizing new mechanistic insights and patient-specific pathways across complexity scales with digital models [3][4][5][6][7], while the final two studies seek to bridge from bench to bedside by examining the links between clinically accessible tissue structure and detailed function [8], as well as pharmaceutical interventions and outcomes [9].…”