In silico study of the mechanisms of hypoxia and contractile dysfunction during ischemia and reperfusion of hiPSC cardiomyocytes.

Interconnected mechanisms of ischemia and reperfusion (IR) has increased the interest in IR in vitro experiments using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We developed a whole-cell computational model of hiPSC-CMs including the electromechanics, a metabolite-sensitive sarcoplasmic reticulum Ca2+-ATPase (SERCA) and an oxygen dynamics formulation to investigate IR mechanisms. Moreover, we simulated the effect and action mechanism of levosimendan, which recently showed promising anti-arrhythmic effects in hiPSC-CMs in hypoxia. The model was validated using hiPSC-CM and in vitro animal data. The role of SERCA in causing relaxation dysfunction in IR was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that levosimendan counteracts the relaxation dysfunction by utilizing a particular Ca2+-sensitizing mechanism involving Ca2+-bound troponin C and Ca2+ flux to the myofilament, rather than inhibiting SERCA phosphorylation. The model demonstrates extensive characterization and promise for drug development, making it suitable for evaluating IR therapy strategies based on the changing levels of cardiac metabolites, oxygen and molecular pathways.

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.

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.

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.

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. 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. METHODS: 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. 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.

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

Coronary artery disease (CAD) is the prevalent reason of mortality all around the world. Targeting CAD, specifically atherosclerosis, with controlled delivery of micro and nanoparticles, as drug carriers, is a very proficient approach. In this work, a patient-specific and realistic model of an atherosclerotic plaque in the left anterior descending (LAD) artery was created by image-processing of CT-scan images and implementing a finite-element mesh. Next, a fluid-solid interaction simulation considering the physiological boundary conditions was conducted. By considering the simulated force fields and particle-particle interactions, the correlation between injected particles at each cardiac cycle and the surface density of adhered particles over the atherosclerotic plaque (SDP) were examined. For large particles (800 and 1000 nm) the amount of SDP on the plaque increased significantly when the number of the injected particles became higher. However, by increasing the number of the injected particles, for the larger particles (800 and 1000 nm) the increase in SDP was about 50% greater than that of the smaller ones (400 and 600 nm). Furthermore, for constant number of particles, depending on their size, different trends in SDP were observed. Subsequently, the distribution and adhesion of metal-based nanoparticles including SiO2, Fe3O4, NiO2, silver and gold with different properties were simulated. The injection of metal particles with medium density among the considered particles resulted in the highest SDP. Remarkably, the affinity, the geometrical features, and the biophysical factors involved in the adhesion outweighed the effect of difference in the density of particles on the SDP. Finally, the consideration of the lift force in the simulations significantly reduced the SDP and consistently decreased the particle residence time in the studied domain.

In silico study of patient-specific magnetic drug targeting for a coronary LAD atherosclerotic plaque.

Coronary artery disease is the first cause of death across the world. Targeted delivery of therapeutics through controlled release of micro- and nano-particles remains a very capable approach to develop new strategies in treating restenosis and atherosclerotic plaques. In this research, to produce the arterial geometry, an image-processing was done using CT-scan images of a LAD coronary artery. After implementing the finite element mesh, the Fluid-Structure Interaction (FSI) simulation based on physiological boundary conditions was performed. Next, a Lagrangian description of particles dynamics in a non-Newtonian blood flow considering momentum equation of motion for each particle and the imposed external magnetic field was provided. Under the influence of the magnetic field, the optimal particle size scope for which the surface density of particles (SDP) adhered on the plaque lumen reaches its maximum was specified. Also, our results signify that applying a magnetic field can adversely affect the delivery of particles to the targeted site for near micron-size particles. Along with the evaluation of the Brownian and the gravitational forces on nanoparticles, the uniformity of the distribution of particles in the left coronary network with and without the presence of the magnetic field has been studied. In conclusion, the external magnetic field has increased the SDP adhered on the targeted surface by 49.4% and 59.7% for 400 and 600 nm particles, respectively.

Personalised deposition maps for micro- and nanoparticles targeting an atherosclerotic plaque: attributions to the receptor-mediated adsorption on the inflamed endothelial cells.

Endothelial inflammation as a prominent precursor to atherosclerosis elicits a distinct pathological surface expression of particular vascular proteins. To exhibit a site-specific behaviour, micro- and nanoparticles, as carriers of therapeutics or imaging agents, can distinguish and use these proteins as targeted docking sites. Here, a computational patient-specific model capturing the exclusive luminal qualities has been developed to study the transport and adsorption of particles decorated with proper antibodies over an atherosclerotic plaque located in the LAD artery of the patient. Particles, in nano- and micron sizes, have been decorated with Sialyl Lewisx (sLex), P-selectin aptamer (PSA), and ICAM-1 antibody (abICAM) to target the three of the most well-known endothelial adhesion proteins that display pathological expressions on the plaque surface, namely E-selectin, ICAM-1, and P-selectin. We learned that in the receptor-mediated adhesive dynamics in pathological contexts, parameters such as specific diffusivity of ligand-receptor pairs and the affinity constant play crucial roles in the final amount and homogeneity of surface density of adsorbed particles (SDA). In spite of ascending nature of SDAs with the increase in particle size, our model specified that the alteration in results due to increase in particle diameter can be insignificant depending upon the special parameters associated with the type of ligand-receptor bonds. Also, the combination of 95.1% sLex and 4.9% PSA ligands for dual-targeting 800-nm particles was introduced as the optimal decorating arrangement for which the surface of plaque experiences a significant SDA along with a homogeneously improved deposition pattern. Finally, the key results of this work were compared with the results of similar experiments in a pulsatile flow chamber and a relevant in vivo test.

Margination and adhesion of micro- and nanoparticles in the coronary circulation: a step towards optimised drug carrier design.

Obstruction of left anterior descending artery (LAD) due to the thrombosis or atherosclerotic plaques is the leading cause of death worldwide. Targeted delivery of drugs through micro- and nanoparticles is a very promising approach for developing new strategies in clot-busting or treating restenosis. In this work, we modelled the blood flow characteristics in a patient-specific reconstructed LAD artery by the fluid-solid interaction method and based on physiological boundary conditions. Next, we provided a Lagrangian description of micro- and nanoparticles dynamics in the blood flow considering their Brownian motion and the particle-particle interactions. Our results state that the number of spherical particles migrating towards the region of lumen with potential of thrombus existence (PTE) rises by increasing the particle size. Also, an optimum scope of particle size in which the adhesive probability parameter reaches its maximum was determined. We acquired an optimum scope for a specific degree of particle sphericity in which the thrombus surfaces experience the maximum density of interaction with particles. We learned that the ligand-receptor mechanism-based drug carriers are better choices for treating LAD arterial diseases when the addressees are patients with low haematocrit-related diseases. While due to the amount of shear stress exerting on the diseased area, generally exploiting nanoshear-activated drug carriers would be the more effective option when it comes to the thrombolytic therapies of patients with high haematocrit-related diseases.