Biology subjects

McCulloch, A. D.

Publications and source records attributed to McCulloch, A. D..

4 recordsLinked to original sources

bioRxiv2026

Statistical Atlas-Based Surrogate Model of Biventricular Wall Mechanics

Here we use a statistical atlas of end-diastolic (ED) and end-systolic (ES) biventricular shapes - previously derived from the UK Biobank imaging substudy - to generate meshes for finite element (FE) simulations of ventricular wall mechanics. The models used the Holzapfel-Ogden constitutive law for passive material properties and a time-varying elastance model of systolic tension development. Simulated ED and ES deformations were projected onto the shape atlas and the principal components were used to train a multi-layer perceptron as a surrogate model. The input layer included shape modes of the unloaded ventricular geometry, and material parameters and ventricular pressures at ED and ES. After training with 444 simulations, the surrogate model achieved a mean square error in predicted displacements of < 2 mm and volumetric overlaps with FE-predicted deformed shapes > 97%, demonstrating good fidelity to the simulated ground truth. This approach may enable accurate prediction of ventricular wall mechanics without computationally expensive finite element analysis, offering a more feasible method for rapid, subject-specific cardiac modeling.

bioengineering↗

bioRxiv2025

Systems modeling of mitochondrial dynamics in different exercise regimes

Exercise stimulates skeletal muscle signaling and mitochondrial metabolism. Emerging evidence shows that mitochondrial dynamics (i.e., fission and fusion) could be regulated by exercise. Yet, there are knowledge gaps on the following questions: (i) which upstream signals are necessary and sufficient to bias mitochondria toward fission versus fusion? (ii) How does cellular energy status and ROS partition control between DRP1 and MFN/OPA1? And (iii) which combinations of intensity and duration produce similar cytosolic signals but distinct mitochondrial remodeling? To address these gaps, we developed an integrative computational framework that connects exercise regimens to mitochondria fission-fusion machinery by linking blood-myofiber energetics in cytosol and mitochondria to skeletal muscle signaling network. The influence of three exercise regimen (i.e., sprint, resistance, and endurance) on mitochondrial fission and fusion was simulated. Classified qualitative validation of signaling network model against studies not used in developing the model achieved 80% accuracy. The model predicts regimen-specific dynamics starting with acute DRP1-driven fission during exercise followed by MFN1/2-OPA1-mediated re-fusion as energy stress declines, consistent with a cyclical triage-then-rebuild paradigm. Changes are most pronounced and sustained with endurance, sharp but brief with sprint, and minimal with resistance. Global sensitivity analysis identified AMPK/PGC-1[->]MFN1/2 as dominant fusion drivers, ROS and AMPK[->]MFF/DRP1 as primary fission switches, and Ca{superscript 2}-calmodulin, ERK, and LKB1/AMPK as shared regulators of fission and fusion. Our model also predicts that an endurance base, augmented with 1-2 weekly high intensity interval traning (HIIT)/ sprint interval training (SIT) sessions could maximize AMPK-ROS pulses and mitochondrial fission-fusion. This framework unifies muscles signaling logic with the energetic state to explain how intensity-volume combinations, bout spacing, and kinase modulation tune mitochondrial remodeling, yielding testable predictions for optimizing training and adjuvant therapies for enhanced human performance.

systems biology↗

bioRxiv2024

Successful Cardiac Resynchronization Therapy Reduces Negative Septal Work in Patient-Specific Models of Dyssynchronous Heart Failure

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches.

bioengineering↗

bioRxiv2020

Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

BackgroundCis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined. MethodsWe performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants. ResultsWe defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner. ConclusionsThis comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

genomics↗