Growth and remodelling of the left ventricle post myocardial infarction

Living organs in human bodies continuously interact with the $in\ vivo$ bio-environment, while reshaping and rearranging their constituents, responding to external or internal stimuli through life cycles. For instance, living tissues adjust the growth (or turnover) rates of their constituents to develop (volumetric and mass) changes as the tissues adapt to the pathological or physiological changes in bio-environment. From the perspective of biomechanics, changes in the bio-environment will induce the growth and remodelling (G\&R) process and reset the mechanical environment. Consequently, the mechanical cues will feed back to G\&R processes. In the long run, the interaction between G\&R and the mechanical response of living organs plays an important role in regulating the organ formulation or pathological growth. To understand the interaction between the mechanical response and the G\&R process, an important ingredient in evaluating the involved mechanics is knowledge of the solid mechanical properties of the soft tissues. Residual stress, resulting from G\&R of soft tissues, is important in modelling the mechanics of soft tissues, which still presents a modelling challenge for including residual stress in cardiovascular applications. For G\&R of living organs, changes of tissue structure and volume are also important determinants for organ development. This raises academic challenges for the understanding of the evolution of material properties and mechanical response of living tissues within a dynamic environment. To investigate the stress states (residual strain or residual stress) of living organs, the experimental results showed that the arterial slices would spring open after cutting along the radial directions, which indicates the residual strain in organs estimated by the opening angle. The residual strain, which is the elastic strain between zero-stress and no-load states, indicates the existence of residual stress after removal of the external loads. The residual stress is considered to modulate the growth and remodelling process in living organs. The evolution of residual stress could relieve the information about the history of growth, which could help to better the understanding of the formation of organs and the development of diseases. Besides the residual stress, G\&R processes are regulated by other factors, while the principles governing those mechanism are still not fully understood. Obviously, improving knowledge in this particular field will give huge potential for the design and optimization of clinical treatments to efficiently save more lives. From a general mechanics perspective to investigate the G\&R process in living tissues, the questions are: How does the residual stress influence the fibre remodelling and the material properties of entire organs? How to determine the combined effects of growth (in the stressed configuration) and remodelling on the fibre structure? How to develop a framework for investigating G\&R processes occurring in the stressed configuration? For arteries, multiple layer models are developed to analytically study residual stress in living organs. For the heart, due to its complex structure and geometry, most previous studies used the unloaded configuration or one-cut configuration as the stress-free configuration to estimate the stress state. However, both experimental and theoretical studies have suggested that: 1) residual stress will significantly influence the stress distribution in the heart. 2) a simple (or single) cut does not release all the residual stress in the heart. We build a multi-cut model and show that multiple cuts are required to release the residual stresses in the left ventricle. Our results show that with the 2-cut and 4-cut models (one radial cut followed by circumferential cuts), agreement with the measured opening angles and radii can be greatly improved. This suggests that a multi-cut model should be used to predict the residual stresses in the left ventricle, at least in the middle wall region. We further show that tissue heterogeneity plays a significant role in the model results, and that an inhomogeneous model with combined radial and circumferential cuts should be used to estimate the correct order of magnitude of the residual stress in the heart. Understanding the healing and remodelling processes induced by myocardial infarction (MI) of the heart is important and the mechanical properties of the myocardium post-MI can be indicative for effective treatments aimed at avoiding eventual heart failure. MI remodelling is a multiscale feedback process between the mechanical loading and cellular adaptation. In this thesis, we use an agent-based model to describe collagen remodelling by fibroblasts regulated by chemical and mechanical cues after acute MI, and upscale into a finite element (FE) 3D left ventricular model. This enables us to study the scar healing (collagen deposition, degradation and reorientation) of a rat heart post-MI. Our results, in terms of collagen accumulation and alignment, compare well to published experimental data. In addition, we show that different shapes of the MI region can affect the collagen remodelling, and in particular, the mechanical cue plays an important role in the healing process. For volumetric growth, recently, when the idea of growth is applied to study the evolution of organ formations, it's usually assumed that growth always occurs in the natural (reference) configuration. In some researches, it is assumed that the growth could release all the residual stress, and that further growth will start from the updated but stress-free configuration. However, living organs are actually exposed to external loading all the time, while the growth should occur from the residually-stressed current configuration. In this thesis, A theoretical framework is developed to calculate the mechanical behaviour of soft tissue after introducing inhomogeneous growth in a residually-stressed current configuration, which avoids assuming that the growth occurs in a `virtual' reference configuration. Moreover, the theoretical framework is introduced to couple the growth and fibre remodelling process to describe the mechanical behaviour of living tissues

Residual stress estimates from multi-cut opening angles of the left ventricle

Purpose: Residual stress tensor has an essential influence on the mechanical behaviour of soft tissues and can be particularly useful in evaluating growth and remodelling of the heart and arteries. It is currently unclear if one single radial cut using the opening angle method can accurately estimate the residual stress. In many previous models, it has been assumed that a single radial cut can release the residual stress in a ring of the artery or left ventricle. However, experiments by Omens et al. (Biomech Model Mechanobiol 1:267–277, 2003) on mouse hearts, have shown that this is not the case. The aim of this paper is to answer this question using a multiple-cut mathematical model. Methods: In this work, we have developed models of multiple cuts to estimate the residual stress in the left ventricle and compared with the one-cut model. Both two and four-cut models are considered. Given that the collagen fibres are normally coiled in the absence of loading, we use the isotropic part of the Holzapfel-Ogden strain energy function to model the unloaded myocardium. Results: The estimated residual hoop stress from our multiple-cut model is around 8 to 9 times greater than that of a single-cut model. Although in principle infinite cuts are required to release the residual stress, we find four cuts seem to be sufficient as the model agrees well with experimental measurements of the myocardial thickness. Indeed, even the two-cut model already gives a reasonable estimate of the maximum residual hoop stress. We show that the results are not significantly different using homogeneous or heterogeneous material models. Finally, we explain that the multiple cuts approach also applies to arteries. Conclusion: We conclude that both radial and circumferential cuts are required to release the residual stress in the left ventricle; using multiple radial cuts alone is not sufficient. A multiple-cut model gives a marked increase of residual stress in a left ventricle ring compared to that of the commonly used single-cut model

Coupled agent-based and hyperelastic modelling of the left ventricle post-myocardial infarction

Understanding the healing and remodelling processes induced by myocardial infarction (MI) of the heart is important, and the mechanical properties of the myocardium post‐MI can be indicative for effective treatments aimed at avoiding eventual heart failure. MI remodelling is a multiscale feedback process between the mechanical loading and cellular adaptation. In this paper, we use an agent‐based model to describe collagen remodelling by fibroblasts regulated by chemical and mechanical cues after acute MI, and upscale into a finite element 3D left ventricular model. We model the dispersed collagen fibre structure using the angular integration method and have incorporated a collagen fibre tension‐compression switch in the left ventricle (LV) model. This enables us to study the scar healing (collagen deposition, degradation, and reorientation) of a rat heart post‐MI. Our results, in terms of collagen accumulation and alignment, compare well with published experimental data. In addition, we show that different shapes of the MI region can affect the collagen remodelling, and in particular, the mechanical cue plays an important role in the healing process

Zoonotic Transmission and Host Switches of Malaria Parasites

Malaria is a deadly disease that affects the health of hundreds of millions of people annually. Five Plasmodium parasite species naturally infect humans: Plasmodium falciparum , Plasmodium vivax , Plasmodium malariae , Plasmodium ovale , and Plasmodium knowlesi. These parasites can also infect various non-human primates. Parasites mainly infecting monkeys, such as Plasmodium cynomolgi and P. knowlesi , the latter of which was considered to be a monkey parasite for years, can also be transmitted to human hosts. Recently, many new Plasmodium species have been discovered in African apes, some of which may be transmitted to humans in the future. Here, we searched PubMed and the internet via Google and selected articles on the zoonotic transmission and evolution of selected malaria parasite species. We review current advances in the relevant topics, emphasizing the transmission of malaria parasites between humans and non-human primates. We also briefly discuss the transmission of some avian malaria parasites between wild birds and domestic fowls. Zoonotic malaria transmission is widespread, thus posing a threat to public health. More studies on parasite species, including their identification in non-human primates, transmission, and evolution, are needed to decrease or prevent the transmission of malaria parasites from non-human primates to humans

An updated Lagrangian constrained mixture model of pathological cardiac growth and remodelling

Progressive left ventricular (LV) growth and remodelling (G&R) is often induced by volume and pressure overload, characterized by structural and functional adaptation through myocyte hypertrophy and extracellular matrix remodelling, which are dynamically regulated by biomechanical factors, inflammation, neurohormonal pathways, etc. When prolonged, it can eventually lead to irreversible heart failure. In this study, we have developed a new framework for modelling pathological cardiac G&R based on constrained mixture theory using an updated reference configuration, which is triggered by altered biomechanical factors to restore biomechanical homeostasis. Eccentric and concentric growth, and their combination have been explored in a patient-specific human LV model under volume and pressure overload. Eccentric growth is triggered by overstretching of myofibres due to volume overload, i.e. mitral regurgitation, whilst concentric growth is driven by excessive contractile stress due to pressure overload, i.e. aortic stenosis. Different biological constituent’s adaptations under pathological conditions are integrated together, which are the ground matrix, myofibres and collagen network. We have shown that this constrained mixture-motivated G&R model can capture different phenotypes of maladaptive LV G&R, such as chamber dilation and wall thinning under volume overload, wall thickening under pressure overload, and more complex patterns under both pressure and volume overload. We have further demonstrated how collagen G&R would affect LV structural and functional adaption by providing mechanistic insight on anti-fibrotic interventions. This updated Lagrangian constrained mixture based myocardial G&R model has the potential to understand the turnover processes of myocytes and collagen due to altered local mechanical stimuli in heart diseases, and in providing mechanistic links between biomechanical factors and biological adaption at both the organ and cellular levels. Once calibrated with patient data, it can be used for assessing heart failure risk and designing optimal treatment therapies

Genome-wide profiling of chromosome interactions in Plasmodium falciparum characterizes nuclear architecture and reconfigurations associated with antigenic variation.

Spatial relationships within the eukaryotic nucleus are essential for proper nuclear function. In Plasmodium falciparum, the repositioning of chromosomes has been implicated in the regulation of the expression of genes responsible for antigenic variation, and the formation of a single, peri-nuclear nucleolus results in the clustering of rDNA. Nevertheless, the precise spatial relationships between chromosomes remain poorly understood, because, until recently, techniques with sufficient resolution have been lacking. Here we have used chromosome conformation capture and second-generation sequencing to study changes in chromosome folding and spatial positioning that occur during switches in var gene expression. We have generated maps of chromosomal spatial affinities within the P. falciparum nucleus at 25 Kb resolution, revealing a structured nucleolus, an absence of chromosome territories, and confirming previously identified clustering of heterochromatin foci. We show that switches in var gene expression do not appear to involve interaction with a distant enhancer, but do result in local changes at the active locus. These maps reveal the folding properties of malaria chromosomes, validate known physical associations, and characterize the global landscape of spatial interactions. Collectively, our data provide critical information for a better understanding of gene expression regulation and antigenic variation in malaria parasites

Polymorphism in a Plasmodium falciparum Erythrocyte-binding Ligand Changes Its Receptor Specificity

Recognition of human erythrocytes by Plasmodium species depends in part on Region II of the Duffy binding-like family of parasite ligands, which includes BA erythrocyte binding ligand (BAEBL) of P. falciparum. In previous studies of BAEBL from two clones, Dd2/Nm from Vietnam and E12 from Papua New Guinea (PNG), it was found that BAEBL bound different erythrocyte receptors. Because of variation in binding specificity, we studied the sequence and erythrocyte binding specificity of Region II of BAEBL in P. falciparum clones from different parts of the world. We observed five nucleotide substitutions leading to five amino acid changes and five polymorphisms in Region II of BAEBL in parasites from both PNG and other parts of the world. We expressed four of the polymorphisms on COS cells and determined their binding to enzyme-treated erythrocytes and to Gerbich-negative erythrocytes. We also performed erythrocyte-binding assay using the native protein from radiolabeled culture supernatant. Both assays demonstrated that each of the four polymorphisms in the parasite ligand, BAEBL, bound to a different receptor on erythrocytes. These results suggest that P. falciparum has evolved multiple invasion pathways dependent on polymorphisms in the BAEBL ligand

cDNA sequences reveal considerable gene prediction inaccuracy in the Plasmodium falciparum genome

<p>Abstract</p> <p>Background</p> <p>The completion of the <it>Plasmodium falciparum </it>genome represents a milestone in malaria research. The genome sequence allows for the development of genome-wide approaches such as microarray and proteomics that will greatly facilitate our understanding of the parasite biology and accelerate new drug and vaccine development. Designing and application of these genome-wide assays, however, requires accurate information on gene prediction and genome annotation. Unfortunately, the genes in the parasite genome databases were mostly identified using computer software that could make some erroneous predictions.</p> <p>Results</p> <p>We aimed to obtain cDNA sequences to examine the accuracy of gene prediction <it>in silico</it>. We constructed cDNA libraries from mixed blood stages of <it>P. falciparum </it>parasite using the SMART cDNA library construction technique and generated 17332 high-quality expressed sequence tags (EST), including 2198 from primer-walking experiments. Assembly of our sequence tags produced 2548 contigs and 2671 singletons <it>versus </it>5220 contigs and 5910 singletons when our EST were assembled with EST in public databases. Comparison of all the assembled EST/contigs with predicted CDS and genomic sequences in the PlasmoDB database identified 356 genes with predicted coding sequences fully covered by EST, including 85 genes (23.6%) with introns incorrectly predicted. Careful automatic software and manual alignments found an additional 308 genes that have introns different from those predicted, with 152 new introns discovered and 182 introns with sizes or locations different from those predicted. Alternative spliced and antisense transcripts were also detected. Matching cDNA to predicted genes also revealed silent chromosomal regions, mostly at subtelomere regions.</p> <p>Conclusion</p> <p>Our data indicated that approximately 24% of the genes in the current databases were predicted incorrectly, although some of these inaccuracies could represent alternatively spliced transcripts, and that more genes than currently predicted have one or more additional introns. It is therefore necessary to annotate the parasite genome with experimental data, although obtaining complete cDNA sequences from this parasite will be a formidable task due to the high AT nature of the genome. This study provides valuable information for genome annotation that will be critical for functional analyses.</p

Modelling of fibre dispersion and its effects on cardiac mechanics from diastole to systole

Detailed fibre architecture plays a crucial role in myocardial mechanics both passively and actively. Strong interest has been attracted over decades in mathematical modelling of fibrous tissue (arterial wall, myocardium, etc.) by taking into account realistic fibre structures, i.e. from perfectly aligned one family of fibres, to two families of fibres, and to dispersed fibres described by probability distribution functions. It is widely accepted that the fibres, i.e. collage, cannot bear the load when compressed, thus it is necessary to exclude compressed fibres when computing the stress in fibrous tissue. In this study, we have focused on mathematical modelling of fibre dispersion in myocardial mechanics, and studied how different fibre dispersions affect cardiac pump function. The fibre dispersion in myocardium is characterized by a non-rotationally symmetric distribution using a π-periodic Von Mises distribution based on recent experimental studies. In order to exclude compressed fibres for passive response, we adopted the discrete fibre dispersion model for approximating a continuous fibre distribution with finite fibre bundles, and then the general structural tensor was employed for describing dispersed active tension. We first studied the numerical accuracy of the integration of fibre contributions using the discrete fibre dispersion approach, then compared different mechanical responses in a uniaxially stretched myocardial sample with varied fibre dispersions. We finally studied the cardiac pump functions from diastole to systole in two heart models, a rabbit bi-ventricle model and a human left ventricle model. Our results show that the discrete fibre model is preferred for excluding compressed fibres because of its high computational efficiency. Both the diastolic filling and the systolic contraction will be affected by dispersed fibres depending on the in-plane and out-of-plane dispersion degrees, especially in systolic contraction. The in-plane dispersion seems affecting myocardial mechanics more than the out-of-plane dispersion. Despite different effects in the rabbit and human models caused by the fibre dispersion, large differences in pump function exist when fibres are highly dispersed at in-plane and out-of-plane. Our results highlight the necessity of using dispersed fibre models when modelling myocardial mechanics, especially when fibres are largely dispersed under pathological conditions, such as fibrosis