A coupled mitral valve - left ventricle model with fluid-structure interaction

Understanding the interaction between the valves and walls of the heart is important in assessing and subsequently treating heart dysfunction. This study presents an integrated model of the mitral valve (MV) coupled to the left ventricle (LV), with the geometry derived from in vivo clinical magnetic resonance images. Numerical simulations using this coupled MV–LV model are developed using an immersed boundary/finite element method. The model incorporates detailed valvular features, left ventricular contraction, nonlinear soft tissue mechanics, and fluid-mediated interactions between the MV and LV wall. We use the model to simulate cardiac function from diastole to systole. Numerically predicted LV pump function agrees well with in vivo data of the imaged healthy volunteer, including the peak aortic flow rate, the systolic ejection duration, and the LV ejection fraction. In vivo MV dynamics are qualitatively captured. We further demonstrate that the diastolic filling pressure increases significantly with impaired myocardial active relaxation to maintain a normal cardiac output. This is consistent with clinical observations. The coupled model has the potential to advance our fundamental knowledge of mechanisms underlying MV–LV interaction, and help in risk stratification and optimisation of therapies for heart diseases

Modelling mitral valvular dynamics–current trend and future directions

Dysfunction of mitral valve causes morbidity and premature mortality and remains a leading medical problem worldwide. Computational modelling aims to understand the biomechanics of human mitral valve and could lead to the development of new treatment, prevention and diagnosis of mitral valve diseases. Compared with the aortic valve, the mitral valve has been much less studied owing to its highly complex structure and strong interaction with the blood flow and the ventricles. However, the interest in mitral valve modelling is growing, and the sophistication level is increasing with the advanced development of computational technology and imaging tools. This review summarises the state-of-the-art modelling of the mitral valve, including static and dynamics models, models with fluid-structure interaction, and models with the left ventricle interaction. Challenges and future directions are also discussed

Whole-heart modelling with valves in a fluid–structure interaction framework

Computational modelling of whole-heart function is a useful tool to study heart mechanics and haemodynamics. Many existing heart models focus on electromechanical aspect without considering physiological valves and use simplified fluid models instead. In this study we develop a four-chamber heart model featuring realistic chamber geometry, detailed valve modelling, hyperelasticity with fibre architecture and fluid–structure interaction analysis. Our model is used to investigate heart behaviours with different modelling assumptions including restricted/free valve annular dynamics, and with/without heart-pericardium interactions. Our simulation results capture the interactions between valve leaflet and surrounding flow, typical left ventricular flow vortices, typical venous and transvalvular flow waveform, and physiological heart deformations such as atrioventricular plane movement. The improvement of ventricular filling and atrial emptying at early diastole is evident with free annulus. In addition, we find that the added pericardial forces on the heart have a predominant effect on atrial wall deformation especially during atrial contraction, and further help with the atrial filling process. Most importantly, the current study provides a framework for comprehensive multi-physics whole-heart modelling considering all heart valves and fluid–structure interactions

Fluid-structure interaction in a fully coupled three-dimensional mitral-atrium-pulmonary model

This paper aims to investigate detailed mechanical interactions between the pulmonary haemodynamics and left heart function in pathophysiological situations (e.g. atrial fibrillation and acute mitral regurgitation). This is achieved by developing a complex computational framework for a coupled pulmonary circulation, left atrium and mitral valve model. The left atrium and mitral valve are modelled with physiologically realistic three-dimensional geometries, fibre-reinforced hyperelastic materials and fluid–structure interaction, and the pulmonary vessels are modelled as one-dimensional network ended with structured trees, with specified vessel geometries and wall material properties. This new coupled model reveals some interesting results which could be of diagnostic values. For example, the wave propagation through the pulmonary vasculature can lead to different arrival times for the second systolic flow wave (S2 wave) among the pulmonary veins, forming vortex rings inside the left atrium. In the case of acute mitral regurgitation, the left atrium experiences an increased energy dissipation and pressure elevation. The pulmonary veins can experience increased wave intensities, reversal flow during systole and increased early-diastolic flow wave (D wave), which in turn causes an additional flow wave across the mitral valve (L wave), as well as a reversal flow at the left atrial appendage orifice. In the case of atrial fibrillation, we show that the loss of active contraction is associated with a slower flow inside the left atrial appendage and disappearances of the late-diastole atrial reversal wave (AR wave) and the first systolic wave (S1 wave) in pulmonary veins. The haemodynamic changes along the pulmonary vessel trees on different scales from microscopic vessels to the main pulmonary artery can all be captured in this model. The work promises a potential in quantifying disease progression and medical treatments of various pulmonary diseases such as the pulmonary hypertension due to a left heart dysfunction

3D-Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma.

The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D-epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carcinoma cell line) using integrative approaches for chromatin topology, genomic and epigenomic variation, and transcriptional output. Comparing the 3D-epigenomes in THLE2 and HepG2 reveal that most HCC-associated genes are organized in complex chromatin interactions mediated by RNA polymerase II (RNAPII). Incorporation of genome-wide association studies (GWAS) data enables the identification of non-coding genetic variants that are enriched in distal enhancers connecting to the promoters of HCC-associated genes via long-range chromatin interactions, highlighting their functional roles. Interestingly, CTCF binding and looping proximal to HCC-associated genes appear to form chromatin architectures that overarch RNAPII-mediated chromatin interactions. It is further demonstrated that epigenetic variants by DNA hypomethylation at a subset of CTCF motifs proximal to HCC-associated genes can modify chromatin topological configuration, which in turn alter RNAPII-mediated chromatin interactions and lead to dysregulation of transcription. Together, the 3D-epigenomic analyses provide novel insights of multifaceted interplays involving genetics, epigenetics, and chromatin topology in HCC cells

Mutation spectrum of PTS gene in patients with tetrahydrobiopterin deficiency from jiangxi province

Background: Hyperphenylalaninemia (HPA) is the most common inborn error in amino acid metabolism. It can be primarily classified into phenylalanine hydroxylase (PAH) deficiency and tetrahydrobiopterin (BH4) deficiency. BH4 deficiency (BH4D) is caused by genetic defects in enzymes involved in the biosynthesis and regeneration of BH4. 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), which is encoded by the PTS gene, participates in the biosynthesis of BH4. PTPS deficiency (PTPSD) is the major cause of BH4D. In this study, we investigated that the prevalence of BH4D in Jiangxi province was approximately 12.5 per 1,000,000 live births (69/5,541,627). Furthermore, the frequency of BH4D was estimated to be 28.8% (69/240) in the HPA population of Jiangxi. In this study, we aimed to characterize the mutational spectrum of the PTS gene in patients with PTPSD from Jiangxi province.Method: Newborn screening data of Jiangxi province from 1997 to 2021 were analyzed and 53 families with PTPSD were enrolled for the analysis of the PTS gene variants by Sanger sequencing.Results: 106 variants were identified in 106 alleles of 53 patients with PTPSD, including 13 types of variants reported previously, and two novel variants (c.164-36A>G and c.146_147insTG). The predominant variant was c.259C>T (47.2%), followed by c.84-291A>G (19.8%), c.155A>G (8.5%), c.286G>A (6.6%) and c.379C>T (4.7%).Conclusion: The results of this study can not only provide guidance for the molecular diagnosis and genetic counseling in cases of PTPS deficiency but also enrich the PTS mutation database

CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer's Disease

Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP beta-cleavage and A beta production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased A beta production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy

Fluid-structure interaction models of mitral valve and left atrium

Mitral valve (MV), together with left atrium (LA) form an important coupled structure inside human heart. Mitral valve dysfunction including mitral stenosis, prolapse and regurgitation, is one of the most common valvular heart disease and hence has attracted significant research interest. Left atrium dysfunction such as atrial fibrillation, fibrosis and dilation, etc., also greatly affects the normal heart performance and leads to serious consequences. Computational modelling of human MV and LA function can improve our understanding of the biomechanics and flow details, which are important for improving surgical procedures and medical therapies. More importantly, it provides a tool for isolating the effects of different physiological and anatomical changes that occur under pathological conditions. However, because of the challenges of modelling the highly complex MV and LA structures and their interaction with the blood flow, only limited progress in multi-physics modelling of MV and LA has been made to date. Therefore, this thesis aims to develop computational models for MV and LA that include detailed geometry information and the fluid-structure interaction (FSI) behaviour as well as to investigate various factors that affect their normal function. First, we present a FSI model of the mitral valve that uses an anatomically and physiologically realistic description of the MV leaflets and chordae tendineae. Three different chordae models --- complex, `pseudo-fibre', and simplified chordae --- are compared to determine how different chordae representations affect the dynamics of the MV. Interesting flow patterns and vortex formulation are observed in all three cases. Additionally, results show that the complex and pseudo-fibre chordae models yield good valve closure during systole, but that the simplified chordae model leads to poorer leaflet coaptation and an unrealistic bulge in the anterior leaflet belly. An energy budget analysis shows that the MV models with complex and pseudo-fibre chordae have similar energy distribution patterns, but the MV model with the simplified chordae consumes more energy, especially during valve closing and opening. To conclude, we find that the complex chordae and pseudo-fibre chordae have similar impact on the overall MV function, but that the simplified chordae representation is less accurate. Following the MV modelling work, we further develop a coupled left atrium - mitral valve model based on coronary computed tomography angiography (CTA). The LA model incorporates patient-specific LA geometry and detailed fibre structure defined by an atlas-based method. It is equipped with a transversely isotropic material model. Effects of pathological conditions, e.g. mitral valve regurgitation and atrial fibrillation, and geometric and structural variations, namely, uniform vs non-uniform atrial wall thickness, atlas-based vs rule-based fibre architectures, on the system are investigated. We show that in the case of atrial fibrillation, the reversal pulmonary venous flow at late diastole disappear and also the filling waves at left atrial appendage orifice during systole have reduced magnitude. In the case of mitral regurgitation, a higher atrial pressure and disturbed flows are seen, especially during systole where a large regurgitant jet can be found with the suppressed pulmonary venous flow. We also show that both the rule-based and atlas-based fibre defining methods lead to similar flow fields and atrial wall deformations. However, the changes in wall thickness from non-uniform to uniform tend to underestimate the atrial deformation. Using a uniform but thickened wall also lowers the overall strain level. The flow velocity within the left atrial appendage, which is important in terms of appendage thrombosis, increases with the thickness of the left atrial wall. Energy analysis shows that the kinetic and dissipation energies of the flow within the left atrium are altered differently under conditions of atrial fibrillation and mitral valve regurgitation, providing a useful indication of the atrial performance in pathological situations. The future development of the coupled model involves applying patient-specific pressure and flow boundary conditions, introducing physiological LV models and modelling the process of blood clotting, etc