Biology subjects

Rosales, R. M.

Publications and source records attributed to Rosales, R. M..

2 recordsLinked to original sources

bioRxiv2025

In silico assessment of arrhythmic risk following the implantation of engineered heart tissues in porcine hearts with varying infarct locations

Engineered heart tissues (EHTs) have shown promise in partially restoring ejection fraction after myocardial infarction (MI); however, their potential to introduce electrophysiological heterogeneities and promote arrhythmias remains underexplored. This study assessed the arrhythmogenic risk following immature EHT engraftment in infarcted ventricles using computational simulations that replicate preclinical protocols. EHT computational models were developed and integrated into nine validated porcine-specific biventricular models from pigs with left circumflex (LCx, n=4) or left anterior descending (LAD, n=5) MIs. Ventricular tachycardia (VT) susceptibility was evaluated using an S1-S2 stimulation protocol across varying pacing sites and coupling intervals, accounting for infarct characteristics, implantation site, conductivity, and the ventricular conduction system (CS). VT burden was quantified with a 0-1 inducibility score (IS). In silico reentrant activity reproduced the arrhythmic patterns observed experimentally in porcine MI models. VT vulnerability was greater in LAD than in LCx infarcts, consistent with a larger infarct size. Inclusion of the CS modified VT burden by providing conduction shortcuts that either facilitated or suppressed reentry. Remuscularization directly on the MI region (IS = 0.49) heightened VT inducibility in dense, transmural scars (IS = 0.16), whereas lateral EHT implantation (IS = 0.35) reduced this risk with respect to direct implantation. In non-transmural scars, VT inducibility varied with the implantation site. Matching EHT conductivity to host myocardium lowered or contained arrhythmogenicity (LCx-IS: from 0.5 to 0.25; LAD-IS: stable at 0.57). These results highlight the latent arrhythmic risk of EHT-mediated remuscularization after MI, identifying infarct substrate, EHT conductivity, and implantation site as critical determinants, and emphasize the importance of incorporating the CS for accurate risk assessment. Author summaryRemuscularization with engineered heart tissue patches has shown preclinical potential to restore cardiac ejection fraction after myocardial infarction. However, the introduction of electrophysiological heterogeneities from these patches remains underexplored. To address this, we performed in silico investigations of post-infarction arrhythmogenesis and its progression after patch engraftment in porcine models with vessel-specific infarcts, applying a comprehensive arrhythmia inducibility protocol. We first computationally reproduced the experimentally observed arrhythmic patterns in pigs. Before patch engraftment, we found that larger infarcts increased ventricular tachycardia vulnerability. The inclusion of the ventricular conduction system modified arrhythmic outcomes, as electrical shortcuts could either facilitate or suppress reentry. Following remuscularization, highly transmural scars exhibited higher arrhythmicity, with lateral patch implantation mitigating it compared to direct placement. In contrast, for poorly transmural scars, the relationship between arrhythmia inducibility and patch location was unclear, highlighting digital twins as a tool for personalized risk prediction. When host-like patch conductivity was used, arrhythmia inducibility after engraftment was reduced or contained. Overall, our results: i) reveal the latent arrhythmogenicity associated with patch-mediated remuscularization of infarcted hearts; ii) identify infarction substrate, patch conductivity, and implantation site as key arrhythmogenic determinants; and iii) emphasize the importance of accurately modeling the cardiac conduction system.

bioengineering↗

bioRxiv2025

Integrated multi-modal data analysis for computational modeling of healthy and location-dependent myocardial infarction conditions in porcine hearts

Porcine hearts are widely used for preclinical cardiac evaluation. Computational models, by effectively integrating comprehensive experimental data, often reinforce this preclinical assessment. Using extensive multi-modal data, we developed swine ventricular digital twins for healthy and chronic myocardial infarction (MI) conditions to investigate the roles of the cardiac conduction system (CS), spatial repolarization heterogeneities, cardiomyocyte orientation, cell-to-cell coupling, and MI characteristics on ventricular function. We analyzed cardiac magnetic resonance (CMR) images, electrocardiograms (ECGs), and optical (OM) and electroanatomical mapping from 5 healthy and 10 MI pigs. CS architectures were built from OM and ECG recordings. Myocardial fiber orientation, action potential characteristics, and cell-to-cell conductivity in MI tissue were defined from OM and CMR data. Simulated ECGs for healthy and MI models of left anterior descending and left circumflex occlusions were compared to experimental ECGs and used to assess MI-induced changes. Personalized fiber orientation minimally affected electrophysiology, with conduction velocity (CV) and action potential duration (APD) changing less than 3.6% with respect to standard orientation. Accurate CS and repolarization heterogeneities reproduced depolarization (0.76 QRS similarity) and repolarization (0.74 T-wave similarity) patterns. Incorporating experimentally guided MI-induced alterations enabled replication of MI depolarization and repolarization features (relative errors: 0.5% CV, 2.9% APD), yielded realistic T-wave morphologies (0.63 similarity), and revealed ECG patterns specific to vessel-dependent occlusions. Thus, by integrating extensive multi-modal data, we advance porcine cardiac digital twins and demonstrate the influence of key structural and electrophysiological parameters on healthy and MI heart function, providing a robust computational framework for mechanistic and translational applications. Author summaryPigs are commonly used as preclinical models for cardiac evaluation due to their close resemblance to the human heart. Computational cardiac electrophysiology often supports and extends this preclinical assessment. However, the reliability of these in silico representations depends on the effective integration of comprehensive experimental data. Using extensive multi-modal data, we developed swine ventricular digital twins under healthy and chronic myocardial infarction conditions. These models allowed us to investigate the influence of the cardiac conduction system, spatial repolarization heterogeneities, cardiomyocyte orientation, cell-to-cell coupling, and vessel-specific infarction characteristics on ventricular function. Our results show that cardiomyocyte orientation exerts only a minor effect on electrophysiology, with average conduction velocity showing a slight decrease and action potential duration remaining unchanged when comparing standard versus personalized orientations. Accurate representation of conduction system architecture and repolarization heterogeneities enabled closed reproduction of experimental depolarization and repolarization patterns. Furthermore, by integrating experimentally guided reductions in cell-to-cell coupling and inward rectifier potassium current, along with personalized post-infarction activation alterations and a novel porcine cellular model, we were able to faithfully replicate infarction-specific depolarization-repolarization features. These refinements produced realistic T-wave morphologies and revealed electrocardiographic signatures associated with vessel-dependent infarctions, underscoring the translational potential of our approach.

bioengineering↗