PO-01-180 MECHANISMS OF PULMONARY ARTERIAL HYPERTENSION-INDUCED ATRIAL FIBRILLATION IN THE RIGHT HEART: INSIGHTS FROM MULTI-SCALE MODELS OF THE HUMAN ATRIA

Abstract

Pulmonary arterial hypertension (PAH) is one of the common conditions primarily affecting the right heart and promoting atrial fibrillation (AF), but the mechanisms are poorly understood. This study aimed to use multi-scale atrial models to investigate mechanisms by which right atrial (RA) remodeling facilitates and perpetuates atrial arrhythmias. We have developed single-cell-to-tissue-level computer models to mimic control and disease conditions by incorporating the most recent experimental data on PAH-induced electrical and structural remodeling (Hiram et al., JACC, 2019). The effects of PAH-induced remodeling in both RA and left atria (LA) on action potential duration (APD), calcium transient (CaT), conduction velocity (CV), and dynamics of re-entrant excitation waves were assessed using the multi-scale computer models. Our computer simulation results suggested that at the single cell level, although PAH-induced remodeling prolonged action potential (ΔAPD: 49.6 ms in the RA vs. 41.6 ms in the LA) and increased calcium transient (ΔCaT: 7.5e-2 μM in the RA vs. 0.9e-3 μM in the LA), heterogeneous remodeling increased susceptibility to afterdepolarizations only in the RA (Fig. A). At the tissue level, dramatically reduced CV (ΔCV: -0.5 m/s in the RA vs. -0.05 m/s in the LA) abbreviated wavelength inthe RA but not inthe LA. In addition, afterdepolarizations in the RA increased repolarization dispersion and promoted unidirectional conduction block (Fig B). Finally, the upregulated fibrosis increased the chance of breakdown of excitation waves and sustained reentries in in the RA (Fig C). These results demonstrated that PAH-induced AF is mainly in RA not LA, due to a higher degree of cardiac remodeling. RA remodeling increases arrhythmias risk due to elevated susceptibility to afterdepolarizations, reduced wavelength, increased repolarization heterogeneity and upregulation of fibrosis, which together facilitate initiation and maintenance of re-entrant circuits in the right heart.