An idealized human cardiomyocyte finite element model for studying the interaction between the cross-bridge state and cell mechanical response.

The mechanical state of cardiomyocyte is directly related to the structure and function of internal sarcomeres. In the field of computational cardiac mechanics, attempts to establish models of human cardiomyocyte with a detailed representation of sarcomere cross-bridge (XB) are rare. In this study, we established a computational model for a cardiomyocyte with idealized geometry while containing a representative sarcomere composed of thick filament, thin filament, titin filament, and Z-disc. The formation of XB with passive tension in the model was simulated with the finite element (FE) method, and stochastic FE analyses were further carried out in conjunction with six sigma analysis to explore the interaction between the S1 power stroke and the twitch mechanics of cardiomyocyte. The proposed modeling method may help us better understand the working state of cardiomyocyte, and offer a potential means for exploring the cell-level mechanisms of cardiac diseases.

The Influence of Aortic Valve Disease on Coronary Hemodynamics: A Computational Model-Based Study.

Aortic valve disease (AVD) often coexists with coronary artery disease (CAD), but whether and how the two diseases are correlated remains poorly understood. In this study, a zero-three dimensional (0-3D) multi-scale modeling method was developed to integrate coronary artery hemodynamics, aortic valve dynamics, coronary flow autoregulation mechanism, and systemic hemodynamics into a unique model system, thereby yielding a mathematical tool for quantifying the influences of aortic valve stenosis (AS) and aortic valve regurgitation (AR) on hemodynamics in large coronary arteries. The model was applied to simulate blood flows in six patient-specific left anterior descending coronary arteries (LADs) under various aortic valve conditions (i.e., control (free of AVD), AS, and AR). Obtained results showed that the space-averaged oscillatory shear index (SA-OSI) was significantly higher under the AS condition but lower under the AR condition in comparison with the control condition. Relatively, the overall magnitude of wall shear stress was less affected by AVD. Further data analysis revealed that AS induced the increase in OSI in LADs mainly through its role in augmenting the low-frequency components of coronary flow waveform. These findings imply that AS might increase the risk or progression of CAD by deteriorating the hemodynamic environment in coronary arteries.

A numerical study of the hemodynamic behavior and gas transport in cardiovascular systems with severe cardiac or cardiopulmonary failure supported by venoarterial extracorporeal membrane oxygenation.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been extensively demonstrated as an effective means of bridge-to-destination in the treatment of patients with severe ventricular failure or cardiopulmonary failure. However, appropriate selection of candidates and management of patients during Extracorporeal membrane oxygenation (ECMO) support remain challenging in clinical practice, due partly to insufficient understanding of the complex influences of extracorporeal membrane oxygenation support on the native cardiovascular system. In addition, questions remain as to how central and peripheral venoarterial extracorporeal membrane oxygenation modalities differ with respect to their hemodynamic impact and effectiveness of compensatory oxygen supply to end-organs. In this work, we developed a computational model to quantitatively address the hemodynamic interaction between the extracorporeal membrane oxygenation and cardiovascular systems and associated gas transport. Model-based numerical simulations were performed for cardiovascular systems with severe cardiac or cardiopulmonary failure and supported by central or peripheral venoarterial extracorporeal membrane oxygenation. Obtained results revealed that: 1) central and peripheral venoarterial extracorporeal membrane oxygenation modalities had a comparable capacity for elevating arterial blood pressure and delivering oxygenated blood to important organs/tissues, but induced differential changes of blood flow waveforms in some arteries; 2) increasing the rotation speed of extracorporeal membrane oxygenation pump (ω) could effectively improve arterial blood oxygenation, with the efficiency being especially high when ω was low and cardiopulmonary failure was severe; 3) blood oxygen indices (i.e., oxygen saturation and partial pressure) monitored at the right radial artery could be taken as surrogates for diagnosing potential hypoxemia in other arteries irrespective of the modality of extracorporeal membrane oxygenation; and 4) Left ventricular (LV) overloading could occur when ω was high, but the threshold of ω for inducing clinically significant left ventricular overloading depended strongly on the residual cardiac function. In summary, the study demonstrated the differential hemodynamic influences while comparable oxygen delivery performance of the central and peripheral venoarterial extracorporeal membrane oxygenation modalities in the management of patients with severe cardiac or cardiopulmonary failure and elucidated how the status of arterial blood oxygenation and severity of left ventricular overloading change in response to variations in ω. These model-based findings may serve as theoretical references for guiding the application of venoarterial extracorporeal membrane oxygenation or interpreting in vivo measurements in clinical practice.

Comparison of algorithms for estimating blood flow velocities in cerebral arteries based on the transport information of contrast agent: An in silico study.

While many algorithms have been proposed to estimate blood flow velocities based on the transport information of contrast agent acquired by digital subtraction angiography (DSA), most relevant studies focused on a single vessel, leaving a question open as to whether the algorithms would be suitable for estimating blood flow velocities in arterial systems with complex topological structures. In this study, a one-dimensional (1-D) modeling method was developed to simulate the transport of contrast agent in cerebral arterial networks with various anatomical variations or having occlusive disease, thereby generating an in silico database for examining the accuracies of some typical algorithms (i.e., time-of-center of gravity (TCG), shifted least-squares (SLS), and cross correlation (CC) algorithms) that estimate blood flow velocity based on the concentration-time curves (CTCs) of contrast agent. The results showed that the TCG algorithm had the best performance in estimating blood flow velocities in most cerebral arteries, with the accuracy being only mildly affected by anatomical variations of the cerebral arterial network. Nevertheless, the presence of a stenosis of moderate to high severity in the internal carotid artery could considerably impair the accuracy of the TCG algorithm in estimating blood flow velocities in some cerebral arteries where the transport of contrast agent was disturbed by strong collateral flows. In summary, the study suggests that the TCG algorithm may offer a promising means for estimating blood flow velocities based on CTCs of contrast agent monitored in cerebral arteries, provided that the shapes of CTCs are not highly distorted by collateral flows.

Noninvasive Assessment of the Fractional Flow Reserve with the CT FFRc 1D Method: Final Results of a Pilot Study.

Background: Until recently, Russia did not utilize noninvasive fractional flow reserve (FFR) assessment. We developed an automated algorithm for noninvasive assessment of FFR based on a one-dimensional (1D) mathematical modeling. Objective: The research aims to evaluate the diagnostic accuracy of this algorithm. Methods: The study enrolled 80 patients: 16 of them underwent 64-slice computed tomography - included retrospectively, 64 - prospectively, with a 640-slice CT scan. Specialists processed CT images and evaluated noninvasive FFR. Ischemia was confirmed if FFR < 0.80 and disproved if FFR ≥ 0.80. The prospective group of patients was hospitalized for invasive FFR assessment as a reference standard. If ischemic, patients underwent stent implantation. In the retrospective group, patients already had invasive FFR values.Statistical analysis was performed using GraphPad Prism 8. We compared two methods using a Bland-Altman plot and per-vessel ROC curve analysis. Considering the abnormality of distribution by the Kolmogorov-Smirnov test, we have used Spearman's rank correlation coefficient. Results: During data processing, three patients of the retrospective and 46 patients of the prospective group were excluded. The sensitivity of our method was 66.67% (95% CI: 46.71-82.03); the specificity was 78.95% (95% CI: 56.67-91.49), p = 0.0052, in the per-vessel analysis. In per-patient analysis, the sensitivity was 69.57% (95% CI: 49.13-84.40); the specificity was 87.50% (95% CI: 52.91-99.36), p = 0.0109. The area under the ROC curve in the per-vessel analysis was 77.52% (95% CI: 66.97-88.08), p < 0.0001. Conclusion: The obtained indices of sensitivity, specificity, PPV, and NPV are, in general, comparable to those in other studies. Moreover, the noninvasive values of FFR yielded a high correlation coefficient with the invasive values. However, the AUC was not high enough, 77.52 (95% CI: 66.97-88.08), p < 0.0001. The discrepancy is probably attributed to the initial data heterogeneity and low statistical power.

Model-based analysis of the sensitivities and diagnostic implications of FFR and CFR under various pathological conditions.

Although fractional flow reserve (FFR) and coronary flow reserve (CFR) are both frequently used to assess the functional severity of coronary artery stenosis, discordant results of diagnosis between FFR and CFR in some patient cohorts have been reported. In the present study, a computational model was employed to quantify the impacts of various pathophysiological factors on FFR and CFR. In addition, a hyperemic myocardial ischemic index (HMIx) was proposed as a reference for comparing the diagnostic performances of FFR and CFR. Obtained results showed that CFR was more susceptible than FFR to the influence of many pathophysiological factors unrelated to coronary artery stenosis. In particular, the numerical study proved that increasing hyperemic coronary microvascular resistance significantly elevated FFR while reducing CFR despite fixed severity of coronary artery stenosis, whereas introducing aortic valve disease only caused a significant decrease in CFR with little influence on FFR. These results provided theoretical evidence for explaining some clinical observations, such as the increased risk of discordant diagnostic results between FFR and CFR in patients with increased hyperemic microvascular resistance, and significant increase in CFR after surgical relief of severe aortic valve disease. When evaluated with respect to the predictive value for hyperemic myocardial ischemia, the performance of FFR was found to be considerably compromised in the presence of severe coronary vasodilation dysfunction or aortic valve disease, whereas the relationship between CFR and HMIx remained relatively stable, suggesting that CFR may be a more reliable indicator of myocardial ischemia under complex pathophysiological conditions.

Comparison of Instantaneous Wave-Free Ratio (iFR) and Fractional Flow Reserve (FFR) with respect to Their Sensitivities to Cardiovascular Factors: A Computational Model-Based Study.

While coronary revascularization strategies guided by instantaneous wave-free ratio (iFR) are, in general, noninferior to those guided by fractional flow reserve (FFR) with respect to the rate of major adverse cardiac events at one-year follow-up in patients with stable angina or an acute coronary syndrome, the overall accuracy of diagnosis with iFR in large patient cohorts is about 80% compared with the diagnosis with FFR. So far, it remains incompletely understood what factors contribute to the discordant diagnosis between iFR and FFR. In this study, a computational method was used to systemically investigate the respective effects of various cardiovascular factors on FFR and iFR. The results showed that deterioration in aortic valve disease (e.g., regurgitation or stenosis) led to a marked decrease in iFR and a mild increase in FFR given fixed severity of coronary artery stenosis and that increasing coronary microvascular resistance caused a considerable increase in both iFR and FFR, but the degree of increase in iFR was lower than that in FFR. These findings suggest that there is a high probability of discordant diagnosis between iFR and FFR in patients with severe aortic valve disease or coronary microcirculation dysfunction.

Non-invasive coronary CT angiography-derived fractional flow reserve: A benchmark study comparing the diagnostic performance of four different computational methodologies.

Non-invasive coronary computed tomography (CT) angiography-derived fractional flow reserve (cFFR) is an emergent approach to determine the functional relevance of obstructive coronary lesions. Its feasibility and diagnostic performance has been reported in several studies. It is unclear if differences in sensitivity and specificity between these studies are due to study design, population, or "computational methodology." We evaluate the diagnostic performance of four different computational workflows for the prediction of cFFR using a limited data set of 10 patients, three based on reduced-order modelling and one based on a 3D rigid-wall model. The results for three of these methodologies yield similar accuracy of 6.5% to 10.5% mean absolute difference between computed and measured FFR. The main aspects of modelling which affected cFFR estimation were choice of inlet and outlet boundary conditions and estimation of flow distribution in the coronary network. One of the reduced-order models showed the lowest overall deviation from the clinical FFR measurements, indicating that reduced-order models are capable of a similar level of accuracy to a 3D model. In addition, this reduced-order model did not include a lumped pressure-drop model for a stenosis, which implies that the additional effort of isolating a stenosis and inserting a pressure-drop element in the spatial mesh may not be required for FFR estimation. The present benchmark study is the first of this kind, in which we attempt to homogenize the data required to compute FFR using mathematical models. The clinical data utilised in the cFFR workflows are made publicly available online.

Biocompatibility of new materials based on nano-structured nitinol with titanium and tantalum composite surface layers: experimental analysis in vitro and in vivo.

A technology for obtaining materials from nanostructured nitinol with titanium- or tantalum-enriched surface layers was developed. Surface layers enriched with titanium or tantalum were shown to provide a decrease in the formation of reactive oxygen species and long-lived protein radicals in comparison to untreated nitinol. It was determined that human peripheral vessel myofibroblasts and human bone marrow mesenchymal stromal cells grown on nitinol bases coated with titanium or tantalum-enriched surface layers exhibit a nearly two times higher mitotic index. Response to implantation of pure nitinol, as well as nano-structure nitinol with titanium or tantalum-enriched surface layers, was expressed though formation of a mature uniform fibrous capsule peripherally to the fragment. The thickness of this capsule in the group of animals subjected to implantation of pure nitinol was 1.5 and 3.0-fold greater than that of the capsule in the groups implanted with nitinol fragments with titanium- or tantalum-enriched layers. No signs of calcinosis in the tissues surrounding implants with coatings were observed. The nature and structure of the formed capsules testify bioinertia of the implanted samples. It was shown that the morphology and composition of the surface of metal samples does not alter following biological tests. The obtained results indicate that nano-structure nitinol with titanium or tantalum enriched surface layers is a biocompatible material potentially suitable for medical applications.