Systematic computational assessment of atrial function impairment due to fibrotic remodeling in electromechanical properties

Abstract

Cardiac fibrosis is a pathological condition associated with many cardiovascular diseases. Atrial fibrosis leads to reduced atrial function, resulting in diminished blood flow and an increased risk of stroke. This reduced function arises from altered myocardial electrophysiological and mechanical properties. Identifying the relative importance of these fibrosis-associated properties can reveal the most significant determinants of left atrial function impairment. In this study, we used a computational framework to investigate the relative importance of various fibrosis-associated properties. Our model, a 3D electromechanical framework coupled with a 0D circulatory model, incorporated patient-specific geometries and fibrosis distributions from clinical imaging data. Nine parameters related to fibrotic remodeling (conduction velocity, ion channel expression levels, cell- and tissue-scale contractility, and stiffness) were analyzed using two sensitivity analysis schemes: a one-factor-at-a-time setup, allowing for analysis of isolated effects, and a fractional factorial design, enabling examination of combined effects. As output, we tracked various metrics derived from model-predicted pressure-volume loops. Impairment of L-type calcium current (ICaL) was most detrimental (up to 64% reduction in A-loop area of the left atrial pressurevolume relationship, quantifying work performed during atrial contraction). Conversely, reduced inward rectifier current (IK1) led to improved atrial function (up to 27% increase in A-loop area). Detailed analysis of spatiotemporal distributions linked these effects to changes in intracellular calcium handling. Fractional factorial design analysis revealed that combination with other parameter changes blunted the impact of reduced ICaL but amplified the impact of reduced IK1. Future research focusing on IK1 and ICaL could be highly significant for clinical and scientific advances. Modeling work can help evaluate left atrial function among larger patient cohorts, focusing on strain analysis. Our work could also be extended to spatiotemporal simulations of blood flow and thrombosis, shedding light onto the mechanisms underlying atriogenic stroke.