High Haematocrit Blood Flow and Adsorption of Micro and Nanoparticles on an Atherosclerotic Plaque : An In-silico Study

Background: The continuing inflammatory response entailed by atherosclerosis is categorised by a pathological surface expression of certain proteins over the endothelium, namely, P-selectins. Thus, to boost the efficiency of drug carriers, these proteins can be used as binding targets. Method: An in-silico patient-specific model of a Left Anterior Descending (LAD) coronary artery considering the luminal unevenness was built and meshed using the finite element method. Objectives: Delivery of particles in a specific size range, from 200 to 3200 nm, covered by P-selectin aptamers (PSA), to an atherosclerotic plaque in a pathologically high haematocrit (Hct) blood flow was simulated. The surface of the plaque was assumed to possess a pathologically high expression of P-Selectins. Results: The distribution of deposited particles over the plaque in high Hct blood was significantly more homogenous compared to that of particles that travelled in normal blood Hct. Moreover, in the high Hct, the increase in the particle size, from 800 nm forwards, had a trivial effect on the upsurge in the surface density of adhered particles (SDAs) over the targeted endothelium. Yet, in normal blood Hct (45% in this research), the increase in the particle diameter from 800 nm forwards resulted in a significant increase in the SDAs over the targeted plaque. Interestingly, unlike the adsorption pattern of particles in normal Hct, a significant distribution of deposited particles in the post-constriction region of the atherosclerotic plaque was observed. Conclusion: Our findings provide insights into designing optimum carriers of anti-thrombotic/inflammatory drugs specifically for high blood Hct conditions.acceptedVersionPeer reviewe

Effect of Material and Population on the Delivery of Nanoparticles to an Atherosclerotic Plaque : A Patient-specific In Silico Study

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Altered contractility in mutation-specific hypertrophic cardiomyopathy : A mechano-energetic in silico study with pharmacological insights

Introduction: Mavacamten (MAVA), Blebbistatin (BLEB), and Omecamtiv mecarbil (OM) are promising drugs directly targeting sarcomere dynamics, with demonstrated efficacy against hypertrophic cardiomyopathy (HCM) in (pre)clinical trials. However, the molecular mechanism affecting cardiac contractility regulation, and the diseased cell mechano-energetics are not fully understood yet.Methods: We present a new metabolite-sensitive computational model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) electromechanics to investigate the pathology of R403Q HCM mutation and the effect of MAVA, BLEB, and OM on the cell mechano-energetics.Results: We offer a mechano-energetic HCM calibration of the model, capturing the prolonged contractile relaxation due to R403Q mutation (∼33%), without assuming any further modifications such as an additional Ca2+ flux to the thin filaments. The HCM model variant correctly predicts the negligible alteration in ATPase activity in R403Q HCM condition compared to normal hiPSC-CMs. The simulated inotropic effects of MAVA, OM, and BLEB, along with the ATPase activities in the control and HCM model variant agree with in vitro results from different labs. The proposed model recapitulates the tension-Ca2+ relationship and action potential duration change due to 1 µM OM and 5 µM BLEB, consistently with in vitro data. Finally, our model replicates the experimental dose-dependent effect of OM and BLEB on the normalized isometric tension.Conclusion: This work is a step toward deep-phenotyping the mutation-specific HCM pathophysiology, manifesting as altered interfilament kinetics. Accordingly, the modeling efforts lend original insights into the MAVA, BLEB, and OM contributions to a new interfilament balance resulting in a cardioprotective effect.publishedVersionPeer reviewe

Sensitivity of the Human Ventricular BPS2020 Action Potential Model to the In Silico Mechanisms of Ischemia.

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Particles in coronary circulation : A review on modelling for drug carrier design

Atherosclerotic plaques and thrombosis are chronic inflammatory complications and the main manifestations of cardiovascular diseases (CVD), the leading cause of death globally. Achieving non/minimal-invasive therapeutic means for these implications in the coronary network is vital and has become an interdisciplinary concern. Accordingly, smart drug delivery systems, specifically based on micro- and nanoparticles, as a promising method to offer non/minimal-invasive therapeutic mechanisms are under active research. Notably, computational models enable us to study, design, and predict treatment strategies based on smart drug delivery systems with less time and cost compared with conventional procedures in interventional cardiology. Also, the optimisation and development of computational methods and models have created a broad and practical insight into patient-specific drug design and therapeutic interventions. This review discusses the most recent works on the transport, dynamics, and delivery of particles as drug carriers to target thrombus, inflamed surfaces, and atherosclerotic plaques. Towards understanding and producing optimised particle-based cardiovascular drug delivery systems, this review conveys an original and multifaceted image on the modelling for drug carrier design.publishedVersionPeer reviewe

A mathematical model of hiPSC cardiomyocytes electromechanics

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are becoming instrumental in cardiac research, human-based cell level cardiotoxicity tests, and developing patient-specific care. As one of the principal functional readouts is contractility, we propose a novel electromechanical hiPSC-CM computational model named the hiPSC-CM-CE. This model comprises a reparametrized version of contractile element (CE) by Rice et al., 2008, with a new passive force formulation, integrated into a hiPSC-CM electrophysiology formalism by Paci et al. in 2020. Our simulated results were validated against in vitro data reported for hiPSC-CMs at matching conditions from different labs. Specifically, key action potential (AP) and calcium transient (CaT) biomarkers simulated by the hiPSC-CM-CE model were within the experimental ranges. On the mechanical side, simulated cell shortening, contraction–relaxation kinetic indices (RT50 and RT25), and the amplitude of tension fell within the experimental intervals. Markedly, as an inter-scale analysis, correct classification of the inotropic effects due to non-cardiomyocytes in hiPSC-CM tissues was predicted on account of the passive force expression introduced to the CE. Finally, the physiological inotropic effects caused by Verapamil and Bay-K 8644 and the aftercontractions due to the early afterdepolarizations (EADs) were simulated and validated against experimental data. In the future, the presented model can be readily expanded to take in pharmacological trials and genetic mutations, such as those involved in hypertrophic cardiomyopathy, and study arrhythmia trigger mechanisms.publishedVersionPeer reviewe

A Novel In Silico Electromechanical Model of Human Ventricular Cardiomyocyte

Contractility has become one of the main readouts in computational and experimental studies on cardiomyocytes. Following this trend, we propose a novel mathematical model of human ventricular cardiomyocytes electromechanics, BPSLand, by coupling a recent human contractile element to the BPS2020 model of electrophysiology. BPSLand is the result of a hybrid optimization process and it reproduces all the electrophysiology experimental indices captured by its predecessor BPS2020, simultaneously enabling the simulation of realistic human active tension and its potential abnormalities. The transmural heterogeneity in both electrophysiology and contractility departments was simulated consistent with previous computational and in vitro studies. Furthermore, our model could capture delayed afterdepolarizations (DADs), early afterdepolarizations (EADs), and contraction abnormalities in terms of aftercontractions triggered by either drug action or special pacing modes. Finally, we further validated the mechanical results of the model against previous experimental and in silico studies, e.g., the contractility dependence on pacing rate. Adding a new level of applicability to the normative models of human cardiomyocytes, BPSLand represents a robust, fully-human in silico model with promising capabilities for translational cardiology.publishedVersionPeer reviewe

The comparison between two mathematical contractile elements Integrated to an hiPSC-CM in silico Model

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