Heart | EPFL Graph Search

The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to the lungs. In humans, the heart is approximately the size of a closed fist and is located between the lungs, in the middle compartment of the chest, called the mediastinum. In humans, other mammals, and birds, the heart is divided into four chambers: upper left and right atria and lower left and right ventricles. Commonly the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart. Fish, in contrast, have two chambers, an atrium and a ventricle, while most reptiles have three chambers. In a healthy heart blood flows one way through the heart due to heart valves, which prevent backflow. The heart is enclosed in a protective sac, the pericardium, which a

Mathematical modeling and numerical simulation of excitation-contraction phenomena in the heart

In this Master thesis we aim at studying some physiological and computational aspects of the excitation-contraction mechanisms in the heart muscle. This phenomenon exhibits many complexities at different spatio-temporal scales. The relevance and applicability of several recent phenomenological and physiologically detailed ionic models will be assessed. The choice of the treated models is based on an equilibrium between results that manage to reproduce correctly the complexity of the cardiac electrophysiology and a weak computational cost in order to solve the large set of ODEs which describe the dynamics of that ionic model. The preferred models include a large part of the more recent electrophysiological discoveries and understandings (e.g. L-type calcium and ryanodine channels) in order to reproduce at best the electrical conduction in the human cardiac tissue based on different experimental or computational measurements. According to these previous remarks, we will perform a thorough testing and quantitative comparison of these models and mechanical activation mechanisms in the framework of the LifeV finite element library. In a second step, a recent model for the description of crossbridge dynamics will be implemented. The importance of using good ionic models makes sense to identify correctly the possible influence on the muscle mechanics activation, which enable the heart to pump blood throughout the entire circulatory system.

2013

Stem cell-based cardiovascular tissue engineering

Thomas Krähenbühl

Cardiovascular diseases, including myocardial infarction, are the leading cause of death worldwide for both men and women. Current therapies are limited by the restricted intrinsic regeneration capacity of the heart and by the lack of organs for transplantation. Human embryonic stem (hES) cells have the capacity to differentiate into various cell types, including vascular cells for forming de novo blood vessels to potentially repair the infarcted heart after myocardial infarction. Our goal was to improve cardiac function after myocardial infarction through hES-based cardiovascular tissue engineering. Our findings summarized: Improved cardiac performance, attenuated left ventricular dilation and decreased infarct size in infarcted rats can be attained after co-injection of hES-derived vascular cells and Thymosin β4 (Tβ4) in matrix metalloproteinase (MMP)-responsive hydrogels. Enhanced vascular cell adhesion, survival and organization can be achieved when coencapsulating bioactive peptide Tβ4 in MMP-responsive matrix in vitro. Directed cardiac differentiation of pluripotent cells can be influenced by matrix elasticity, adhesion ligand concentration and MMP-sensitivity in vitro. We first systematically modulated a three-dimensional (3D) MMP-responsive hydrogel, mimicking key biochemical characteristics of natural collagenous matrices, the major constituent of cardiac extracellular matrices. We found that these synthetic poly(ethylene glycol) (PEG)-based hydrogels can direct differentiation of pluripotent cardioprogenitors, using P19 embryonal carcinoma (EC) cells as a model, along a cardiac lineage in vitro. In order to systematically probe 3D matrix effects on P19 EC differentiation, matrix elasticity, MMP-sensitivity and the concentration of a matrix-bound RGDSP peptide, which is relevant in early cardiac developments were modulated. Soft matrices (E = 320 ± 64 Pa), mimicking the elasticity of embryonic cardiac tissue, increased the fraction of cells expressing the early cardiac transcription factor Nkx2.5 around 2-fold compared to embryoid bodies (EB) in suspension. In contrast, stiffer matrices (E = 4040 ± 420 Pa) decreased the number of Nkx2.5-positive cells significantly. Further indicators of cardiac maturation were promoted by ligation of integrins relevant in early cardiac development (α5β1, αvβ3) by the RGDSP ligand in combination with the MMP-sensitivity of the matrix, with a 6-fold increased amount of myosin heavy chain (MHC)-positive cells as compared to EB in suspension. This precisely controlled 3D culture system thus may serve as a potential alternative to natural matrices for engineering cardiac tissue structures for cell culture and potentially therapeutic applications. Neovascularization of infarcted tissue is a promising alternative strategy to potentially restoring lost contractile performance by cardiac cells. Vascular cells and cytokines are known to contribute to the protection of cardiomyocytes from death after myocardial infarction, but also in endogenous recruitment of vascular cells and even cardiomyocytes. The in vitro potential of the synthetic MMP-responsive PEG-hydrogel as a bioactive co-encapsulation system for vascular cells and a small bioactive peptide, Tβ4, was then examined. Tβ4 was previously shown to enhance survival of vascular cells and cardiomyocytes in ischemic environments, stimulate neovascularization after cardiac injury by inducing endogenous endothelial cell migration to the ischemic site, as well as play a key role in down-regulating expression of inflammatory molecules. We show that the physical incorporation of Tβ4 in this bioactive matrix creates a 3D environment conducive for human umbilical vein endothelial cell (HUVEC) adhesion, survival, migration and organization. Gels with entrapped Tβ4 increased the survival of HUVEC compared to gels without Tβ4 (p < 0.05), and significantly up-regulated the endothelial genes vascular endothelial-cadherin and angiopoietin-2, whereas the von Willebrand factor was significantly down-regulated (all p < 0.05). Incorporation of Tβ4 significantly increased MMP-2 and MMP-9 secretion of encapsulated HUVEC (p < 0.05). The gel acts as a controlled Tβ4-release system, as MMP-2 and MMP-9 enzymes trigger the release. In addition, Tβ4 facilitated HUVEC attachment and induced vascular-like network formation upon the PEG-hydrogels. These MMP-responsive PEG-hydrogels may thus serve as controlled co-encapsulation system of vascular cells and bioactive factors for in situ regeneration of ischemic tissues. Finally, we employed these injectable MMP-responsive bioactive hydrogels with vasculo-typic adhesion molecule as a provisional in situ reservoir of vascular cells derived from hES cells and Tβ4 peptide, in infarcted hearts. Typically, after myocardial infarction, the performance-generating contractile cardiac tissue is partially replaced by non-contractile fibrotic tissue, driven by upregulated enzymes such as MMP. Here, magnetic resonance imaging (MRI) revealed enhanced contractile performance 3 days and 6 weeks after myocardial infarction (both p < 0.001), attenuated left ventricular dilation (p < 0.05) and decreased infarct size at 6 weeks (p < 0.05) as compared to infarcted rats with PBS injection. . We found the gel substituting the native degrading extracellular matrix in the infarcted myocardium and promoting structural organization of endothelial cells and cardiomyocytes, while the delivered hES-derived vascular cells formed de novo capillaries in the infarct zone.

EPFL2009

Effects of a stiffened arterial tree on ventricular-arterial coupling in healthy and diseased hearts

David Jegger

In this thesis we study ventricular-arterial coupling in rodents under the influence of arterial stiffening and myocardial infarction (MI), combination of the two considered as a novel cardiovascular research model for diseased hearts pumping against an aged, stiffened arterial tree. The stiffened arterial tree yields isolated systolic hypertension and is obtained by administration of vitamin D and nicotine (VDN). The investigation cardiac performance and ventricular-arterial coupling using such a combined model (VDN/MI) is of particular relevance to cardiac research, as cardiac disease in elderly often takes place in presence of a atherosclerotic or stiff arterial tree.. The thesis consists of an Introduction, 4 scientific papers and a brief Conclusion. The Introduction is an overview of the epidemiology of heart failure, structure and functional changes that occur during MI and VDN, material and methods used in evaluating cardiac function invasively and non-invasively (using trans-thoracic echocardiography, TTE), methods for evaluating arterial function, and finally an overview of the interaction between the heart and vessels. Paper 1: This paper addresses the issue of the universality of the normalized time-varying elastance curve. It is demonstrated that the waveform of the normalized time-varying elastance curve (En(tn)) is qualitatively comparable between the control and MI hearts, however, when En(tn) is compared quantitatively between the two groups, statistical significance is found at the ejection phase and during diastole. These differences need to be taken into account when assessing cardiac contractility based on a generalized En(tn) in different animal models or in the human in different physiological or pathological states. Paper 2: Using trans-thoracic echo (TTE), we were able to follow serial changes of cardiac function post MI using two novel parameters, the myocardioal performance index (MPI) and its ratio to left ventricular fractional shortening (LVFS/MPI), both indices being monitor successfully and as efficiently as other classical TTE parameters. More so, LVFS/MPI visually expressed better the serial modifications in cardiac function. Both MPI and LVFS/MPI were correlated to the load-independent contractile parameter, PRSW, and to the preload parameter, LVEDP, being thus pertinent in following preload changes post MI. Finally, chamber remodeling post MI can successfully be followed due to the fact that ESV and EDV both correlate to MPI and LVFS/MPI. Paper 3: We studied hemodynamics, arterial function, cardiac function and ventricular-arterial coupling in a rat model of reduced arterial compliance. The results show that arterial stiffening after VDN treatment provokes important changes in vascular impedance and wave reflections, leading to isolated systolic hypertension and LV hypertrophy, Ventricular-arterial coupling was also altered. The effects are quantitatively similar to those of arterial stiffening with age. Paper 4: We studied changes in cardiac geometry, structure and function in response to MI in control and VDN-treated (stiffened aorta) rats. The combined VDN/MI model showed the largest compromise in cardiac structure and function and exhibited the strongest biochemical signs of heart failure as compared to all other groups. The addition of MI on top of a raised afterload, seems to have accelerated the progression of heart failure. Vascular alterations also reflected well a model of ageing and calcification. This combined pathology model of failing hearts in presence of a stiff arterial tree might be fruitful in better understanding the evolution of disease and may help improving or developing novel treatment therapies. The Conclusion chapter summarizes the findings of the thesis and brings into perspective their importance and future relevance into cardiovascular research models.

EPFL2006