Biology subjects

Niederer, S. A.

Publications and source records attributed to Niederer, S. A..

5 recordsLinked to original sources

bioRxiv2026

OpenCRS: an open-source regulated human cardiorespiratory model with large-scale calibration and global sensitivity analysis at rest and during exercise

Cardiopulmonary exercise testing reveals cardiovascular and respiratory limitations not apparent at rest, but similar measurements can arise from different interacting regulatory mechanisms, preventing physiological causal inference from data alone. Mechanistic computational models can separate these mechanisms in silico. However, whole-body cardiorespiratory models contain hundreds of parameters, making global sensitivity analysis and calibration challenging. We present OpenCRS, an open-source Python cardiorespiratory model coupling closed-loop 0D lumped-parameter circulation with gas exchange and integrated autonomic and respiratory control. The framework incorporates baroreflex, chemoreflex, pulmonary stretch receptors, central command, and neuromuscular drive, together with novel representations of atrial dynamics and exercise baroreflex set-point resetting. We introduce a scalable calibration pipeline that (i) applies a derivative-based global sensitivity measure (DGSM) directly to the simulator, reducing 272 parameters to 72 influential ones; (ii) trains Gaussian process emulator surrogates within iterative History Matching to exclude implausible parameter regions; and (iii) performs Bayesian calibration (MCMC), inferring a joint posterior with Hamiltonian Monte Carlo (No-U-Turn sampler) under a Gaussian copula prior. A single maximum a posteriori parameter set simultaneously reproduced 50 literature-derived rest and exercise targets (45/50 within 1 SD, all within 1.83 SD), with the rest-to-exercise transition emerging from the models embedded feedback rather than independent fitting. Simulator-based DGSM agreed with constrained Sobol indices (mean Spearman rank correlation 0.79). Sensitivity analysis identified influential physiological mechanisms. Only 2-16 parameters contributed >2% of the Sobol total-effect sensitivity per target. Resting cardiovascular targets were driven by unstressed volumes and cardiac mechanics, while exercise shifted influence towards autonomic efferent regulation. Respiratory outputs remained most sensitive to chemoreflex and gas exchange parameters. These shifts capture coordinated cardiorespiratory adaptation to metabolic demand. More broadly, the framework provides a population-level prior with quantified uncertainty for cardiovascular digital twins and a reusable route for calibrating high-dimensional, regulated physiological models.

systems biology↗

bioRxiv2026

The Ca2+-Sensitivity of Contraction is Increased in the Left Atrium and Left Ventricle of Patients with Ischemic Heart Failure

BackgroundIschemic heart failure (IHF) has been shown to impair contractility and disrupt sarcomere function in the left ventricle. Left ventricular failure can cause left atrial dysfunction, which is associated with a greater risk of patient mortality. Despite this, the biochemical and biomechanical characteristics of the left atrium in IHF remain obscure. MethodsMyocardial mechanical properties were measured using permeabilized muscle isolated from the left ventricle (LV) and left atrium (LA) of donors and patients with IHF. Tissue homogenates from these samples were used to measure titin and myosin isoforms as well as the phosphorylation of sarcomeric regulatory proteins. Histology was used to quantify fibrosis in the patients left ventricle and left atrium. ResultsLength-dependent changes in Ca2+-sensitivity were blunted in LV myocardium from patients with IHF. LA myocardium did not show robust length-dependence of Ca2+-dependent force. The calcium sensitivity of both LA and LV myocardium was increased in IHF. The maximum force generated by LV but not LA myocardium was decreased in IHF. LA myocardial samples exhibited faster contractile kinetics than LV samples, irrespective of disease. Troponin I phosphorylation decreased in both chambers with IHF. ConclusionsLeft atrial IHF myocardium maintained contractile force and displayed increases in calcium sensitivity, which may allow for increased LA contraction under pathological conditions. The increases in calcium sensitivity observed in ischemic myocardium of both chambers are likely driven by decreased phosphorylation of troponin I, which alters thin filament regulation. Conversely, thick filament properties of the left ventricle, such as thick filament protein isoforms and phosphorylation of myosin binding protein-C, displayed chamber-specific differences independent of disease state. These biochemical changes may explain the chamber-specific differences in kinetics and length-dependent properties. Collectively, these biophysical and biochemical data suggest LA remodeling in IHF may assist in increasing LV end-diastolic volume to maintain adequate cardiac output.

physiology↗

bioRxiv2026

A Cohort-Based Global Sensitivity Benchmark of MRI-Derived Whole-Heart Electromechanical Models in Healthy Hearts

Patient-specific four-chamber electromechanical models provide a physics-constrained framework for investigating whole-heart cardiac physiology and disease mechanisms. Identifying which model parameters impact whole-heart function is important for understanding cellular-, tissue-, and organ-scale determinants of cardiac performance and for calibrating patient-specific models. However, previous global sensitivity analyses of cardiac electromechanical models have typically been performed on a single heart, and systematic evaluation of how parameter influence compares across anatomically different subjects remains limited. We created four-chamber electromechanical models using cardiac MRI from five healthy subjects (n = 5). The models simulated atrial and ventricular cellular electrophysiology, calcium dynamics, and active contraction, with heterogeneous fibre orientation, transversely isotropic tissue mechanics, pericardial constraint, and a closed-loop cardiovascular system providing physiological boundary conditions. In total, 46 parameters described the integrated model. Using Gaussian process emulators, we performed multi-scale global sensitivity analysis to evaluate the relative contribution of model parameters to left and right atrial and ventricular function. Across all anatomies, the most influential parameters were systemic and pulmonary resistances, ventricular end-diastolic pressures, and the venous reference pressure, highlighting the dominant role of haemodynamic loading conditions in governing pressure- and volume-based outputs. A chamber-level analysis of atrioventricular coupling revealed a phase-dependent pattern. Atrial pressures were predominantly governed by global haemodynamic parameters (> 90% of total sensitivity), atrial filling volumes showed substantial ventricular influence ({approx}40-55% across anatomies), and atrial end-systolic volumes were primarily determined by intrinsic atrial parameters ({approx}60-65%). These patterns were consistent across subjects despite differences in anatomy. We show that, in healthy male subjects, inter-individual anatomical variation does not substantially change the ranking of dominant parameters. This work provides a repeatable modelling and sensitivity analysis framework and establishes a benchmark reference for whole-heart electromechanical modelling in healthy hearts. Author summaryComputational models of the heart can simulate cardiac physiology in unprecedented detail, but these models contain many parameters whose influence on predicted function is not fully understood. We built patient-specific four-chamber heart models from MRI scans of five healthy subjects and used statistical methods to systematically test how 46 model parameters affect simulated cardiac performance. Across all five subjects, we found that the haemodynamic loading parameters, including systemic and pulmonary vascular resistance, ventricular filling pressures, and the venous reference pressure, consistently had the greatest influence on the model outputs, regardless of differences in individual heart anatomy. This finding suggests that in healthy resting conditions, the boundary conditions of the cardiovascular system, rather than individual differences in heart geometry or electrical properties, are the primary drivers of whole-heart function. We also found a structured coupling pattern between the upper and lower heart chambers, where global haemodynamic parameters dominate atrial pressure regulation, ventricular mechanics shape atrial filling, and intrinsic atrial properties control atrial emptying. This work provides a benchmark dataset of five anatomically detailed heart models and a sensitivity analysis framework to guide calibration of future cardiac digital twin models.

systems biology↗

bioRxiv2026

Resident cardiac macrophages are not required for normal atrioventricular node conduction

Resident cardiac macrophages are understood to facilitate atrioventricular (AV) node conduction because they purportedly couple to AV node myocytes via connexin43 (Cx43) containing gap junctions. We tested this mechanism using biophysical modelling, high-resolution imaging of mouse and human AV conduction tissue, and pharmacological macrophage depletion. In silico, coupling macrophage membrane phenotypes to HCN4+ AV node myocytes imposed an electrotonic load that suppressed pacemaking and promoted conduction slowing, including stable 2:1 block in strand simulations. Anatomically, HCN4-defined components of the mouse AV conduction axis were essentially devoid of Cx43 and overlap of CD68+ macrophages and Cx43 was negligible in both mouse AV node and human penetrating bundle. Finally, near-complete macrophage depletion with CSF1R inhibition (PLX5622) did not alter AV electrical activity in vivo or ex vivo. Together, these data argue against a physiologically relevant role for Cx43-mediated macrophage-myocyte electrical coupling in normal AV node function. HIGHLIGHTSO_LIModelling predicts that AV node automaticity and conduction would be suppressed if macrophages coupled to AV node myocytes C_LIO_LIThe mouse AV conduction axis is essentially devoid of Cx43, currently considered responsible for macrophage-AV node myocyte coupling C_LIO_LIOverlap of macrophages and Cx43 expression is not discernible in the Cx43-expressing human distal AV node C_LIO_LIMacrophage depletion by CSF1R inhibition does not impact AV electrical activity in vivo or ex vivo C_LI

physiology↗

bioRxiv2023

Neural network emulation of the human ventricular cardiomyocyte action potential: a tool for more efficient computation in pharmacological studies

AbstractComputer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimental data can become a significant computational burden. To mitigate the computational burden, the present study introduces a neural network (NN) that emulates the AP for given maximum conductances of selected ion channels, pumps, and exchangers. Its applicability in pharmacological studies was tested on synthetic and experimental data. The NN emulator potentially enables massive speed-ups compared to regular simulations and the forward problem (find drugged AP for pharmacological parameters defined as scaling factors of control maximum conductances) on synthetic data could be solved with average root-mean-square errors (RMSE) of 0.47 mV in normal APs and of 14.5 mV in abnormal APs exhibiting early afterdepolarizations (72.5% of the emulated APs were alining with the abnormality, and the substantial majority of the remaining APs demonstrated pronounced proximity). This demonstrates not only very fast and mostly very accurate AP emulations but also the capability of accounting for discontinuities, a major advantage over existing emulation strategies. Furthermore, the inverse problem (find pharmacological parameters for control and drugged APs through optimization) on synthetic data could be solved with high accuracy shown by a maximum RMSE of 0.21 in the estimated pharmacological parameters. However, notable mismatches were observed between pharmacological parameters estimated from experimental data and distributions obtained from the Comprehensive in vitro Proarrhythmia Assay initiative. This reveals larger inaccuracies which can be attributed particularly to the fact that small tissue preparations were studied while the emulator was trained on single cardiomyocyte data. Overall, our study highlights the potential of NN emulators as powerful tool for an increased efficiency in future quantitative systems pharmacology studies.

cell biology↗