Biology subjects

Boyle, P.

Publications and source records attributed to Boyle, P..

3 recordsLinked to original sources

bioRxiv2026

Fibrosis burden and spatial pattern affect left atrial appendage stasis in multi-beat multi-physics simulations

Purpose: Atrial fibrosis is associated with thromboembolic risk in atrial fibrillation, but how fibrosis-related contractile impairment alters blood transport in the left atrium (LA) and left atrial appendage (LAA) remains unclear. Prior multi-physics simulations coupled electromechanical (EM) and computational fluid dynamics (CFD) models to show that fibrosis impairs LA function and flow, but were limited to booster-only contraction and could not separate the effects of fibrosis burden from its spatial distribution. Here we examined how fibrosis burden and spatial pattern independently relate to long-term LA and LAA hemodynamics in full-cycle, multi-beat simulations on a common LA anatomy. Methods: Three fibrosis patterns derived from late gadolinium enhancement MRI were considered: one from the patient providing the common anatomy and two from additional patients, with the latter mapped onto the common anatomy via universal atrial coordinates. All three patterns were applied globally at matched burdens of 15.6% and 31.2%, yielding six global-fibrosis cases and a non-fibrotic reference. Two patterns were also confined to the LAA at three local burdens (10%, 25%, and 50%), yielding six LAA-fibrosis cases. A 3D EM model for the LA anatomy was coupled to a 0D circulatory model, so that the simulations resolved the reservoir, conduit, and booster phases. Full-cycle EM-derived wall motion drove subsequent multi-beat CFD simulations. Region-specific emptying fraction (EF), non-dimensional kinetic energy (KE), and the 90th percentile of blood residence time (TR) were evaluated for the LA and LAA. Results: Left ventricular stroke volume remained nearly constant across cases, while increasing global fibrosis burden progressively reduced LA and LAA EF (LA: 36% to 30-31%; LAA: 44% to 28-38%) and monotonically increased LA TR across all patterns. Non-dimensional LA KE showed an approximately quadratic association with LA EF across patterns, whereas LAA KE was more scattered but still increased with LAA EF. In contrast, the relationship between the 90th percentile of LAA TR and LAA EF showed pattern-specific, non-monotonic trends. Conclusions: Fibrosis burden and spatial distribution jointly shape LA and LAA hemodynamics, but through different mechanisms. LAA EF is a robust functional descriptor of chamber-averaged kinetic energy regardless of fibrosis pattern, whereas LAA blood stasis depends additionally on the spatial distribution of fibrosis beyond what bulk emptying fraction predicts. These findings support incorporating imaging-derived fibrosis pattern, and not only burden, alongside functional metrics when assessing thrombogenic risk in the LAA.

bioengineering↗

bioRxiv2025

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

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 the analysis of isolated effects, and a fractional factorial design, enabling the 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). Conversely, reduced inward rectifier current (IK1) led to improved atrial function (up to 27% increase in A-loop area). Fractional factorial design analysis revealed that combination with other parameter changes blunted the impact of reduced ICaL but amplified the impact of reduced IK1. Further analysis of spatiotemporal distributions linked these effects to changes in intracellular calcium handling. Future research focusing on IK1 and ICaL could be highly significant for clinical and scientific advances. Modeling work can potentially 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. Author summaryCardiac fibrosis is a process where healthy heart muscle is replaced with non-conductive, non-contractile tissue. This change disrupts how the heart beats and contracts. In the left atrium, fibrosis is strongly linked to atrial fibrillation and a higher risk of stroke, the latter due to impaired pumping and altered blood flow. In this study, we used a detailed computer model of the heart, based on real patient-specific left atrial shapes and fibrosis patterns, to understand how different fibrosis-related changes affect atrial function. We tested nine features of the hearts electrical and mechanical behavior that are known to change during fibrosis, aiming to identify which ones have the most impact on the atrial function. We found that reducing the L-type calcium current -- an important signal for muscle contraction -- caused the greatest decrease in atrial performance. Surprisingly, reducing the inward rectifier potassium current actually improved it. These effects were tied to changes in calcium handling inside heart cells. Our findings highlight promising directions for future heart disease research and treatment.

systems biology↗

bioRxiv2019

Brain microRNAs associated with late-life depressive symptoms are also associated with cognitive trajectory and dementia

ObjectiveLate-life depression is associated with an increased risk for dementia, but our knowledge of the molecular mechanisms underlying this association is limited. Hence, the authors investigated whether microRNAs, important post-transcriptional regulators of gene expression, contribute to this association.\n\nMethodLate-life depressive symptoms were assessed annually in 300 non-demented participants of the Religious Orders Study and Rush Memory and Aging Project for a mean of seven years using the Center for Epidemiological Studies Depression scale. Participants underwent annual cognitive testing, clinical assessment of cognitive status, and uniform neuropathologic examination after death. microRNAs were profiled from the prefrontal cortex using Nanostring platform. A global microRNA association study of late-life depressive symptoms was performed using linear mixed model adjusting for sex, age, Alzheimers dementia pathological burden, proportions of brain cell types, post-mortem interval, and RNA integrity.\n\nResultsFour brain microRNAs were associated with late-life depressive symptoms at adjusted p<0.05 (miR-484, miR-26b, miR-30d, and miR-197). Lower expressions of these miRNAs were associated with greater depressive symptoms. Furthermore, lower expressions of miR-484 and miR-197 were associated with faster decline of cognitive performance over time. Additionally, lower miR-484 level was associated with higher probability of having Alzheimers dementia. Lastly, the predicted targets of miR-484 were enriched in a brain protein co-expression module involving synaptic transmission and regulation of long-term neuronal synaptic plasticity.\n\nConclusionsThis is the first study to identify brain microRNAs associated with late-life depressive symptoms assessed longitudinally. Additionally, the authors found a link between late-life depressive symptoms and dementia through miR-484 and miR-197.

genomics↗