Rozprawy doktorskie na temat „Ventricles”

Two models of electrical conduction in the cardiac ventricles are considered. The first model considered is that of a strand of ventricular muscle which uses the one-dimensional cable equation with the Beeler-Reuter model to represent the transmembrane currents. The effect of periodic stimulation on the strand is numerically simulated, and it is found that as simulation frequency is increased, the rhythms of synchronization are successively encountered. It is shown that this sequence of rhythms can be accounted for by considering the response of the strand to premature stimulation. This involves deriving a one-dimensional finite-difference equation or "map" from the response to premature stimulation, and then iterating this map to predict the response to periodic stimulation.
The second model states that the highly ramified His-Purkinje system is reminiscent of a fractal branching structure, and that the ventricular myocardium is activated in a "fractal" (time-scale invariant) fashion, since it is activated via the His-Purkinje system. A 1/$f sp alpha$ power spectrum can sometimes be linked to fractal processes. The averaged power spectrum of single QRS complexes falls off as 1/$f sp alpha$ ($ alpha sim$ 4).

Statistical data from clinical studies indicate that the death rate caused by heart disease has decreased due to an increased use of evidence-based medical therapies. This includes the use of magnetic resonance imaging (MRI), which is one of the most common non-invasive approaches in evidence-based health care research. In the current work, I present 3D Lagrangian strains and torsion in the left ventricle of healthy and isoproterenol-stimulated rats, which were investigated using Displacement ENcoding with Stimulated Echoes (DENSE) cardiac magnetic resonance (CMR) imaging. With the implementation of the 12-segment model, a detailed profile of regional cardiac mechanics was reconstructed for each subject. Statistical analysis revealed that isoproterenol induced a significant change in the strains and torsion in certain regions at the mid-ventricle level. In addition, I investigated right ventricular cardiac mechanics with the methodologies developed for the left ventricle. This included a comparison of different regions within the basal and mid-ventricular regions. Despite no regional variation found in the peak circumferential strain, the peak longitudinal strain exhibited regional variation at the anterior side of the RV due to the differences in biventricular torsion, mechanism of RV free wall contraction, and fiber architecture at RV insertions. Future applications of the experimental work presented here include the construction and validation of biventricular finite element models. Specifically, the strains predicted by the models will be statistically compared with experimental strains. In addition, the results of the present study provide an essential reference of RV baseline evaluated with DENSE MRI, a highly objective technique.

Until recently, the only realistic form of treatment available to patients in end stage heart failure was transplantation. In the last few years, the possibility of diverting skeletal muscle from its normal function to perform a cardiac assist role has emerged as a potential alternative to transplant surgery. The introduction of an Skeletal Muscle Ventricle (SMV) to the circulation is a potential long-term hazard, as the patient's blood comes into contact with the non-endothelialised surfaces of the wall of the new ventricle and the connecting conduits. This may trigger a cascade of events leading to deposition of thrombus, whose formation is dependent on the nature of the blood flow. The potential problem of haemostasis may arise in the apex of the artificial ventricle, where little mixing and large residence times may occur. There is therefore a strong need for carrying out flow analysis studies to address in detail the questions of haemostasis and thrombogenesis and in this context to evaluate possible candidate SMV configurations. Research on the dynamics of the flow inside model SMVs has been carried out on physical and numerical models with the objective of aialysing the effect of the size and shape of the ventricle and inlet/outlet orientation of the duct. Due to the physiological limit on the power available to pump the blood out of the ventricle, the efficiency of these potential assistance devices has to be maximized. It is also necessary to minimize the risks of haemolysis and thrombogenesis, which are both related, in different ways, to the level of shear stress on the wall and within the flow. A common feature of these flows is the formation of vortex rings. Vortices enhance mixing, and this is a useful process to encourage in an SMV, as it could assist in the mixing of the blood components and in the reduction of apical residence time. Being able to predict accurately the dynamics of the vortices is therefore important, as this will affect the prediction of residence times and shear stresses at the wall and within the flow. It is also very important to know whether numerical codes can predict vortex ring dynamics from both qualitative and quantitative points of view. In order to study the dynamics of the formation of these vortices, first, mathematical models were studied. The general purpose CFDS-FLOW3D code was used in all numerical simulations. Initial investigations of this research project concerned a progressive validation of the numerical solution predicted by the code when the domain where the flow is calculated had moving boundaries. Firstly, comparisons were made with the analytical solution for expanding/contracting pipes. An adapted compliant SMV model was then generated with a truncated apex using sinusoidally prescribed motion of the wall. With this model, two vortex rings could be predicted as in the experiments. The spherical-end model also gave good agreement with experimental flow patterns (ludicello et al., 1994). Frequency-dependent studies were carried out over the range of cardiac values using single- and multi-block versions of the code. A further validation exercise involved the use of sigmoidal filling curves in the in vitro models (Shortland et a!., 1994). Experimental data provided by such studies were used to drive the wall motion in the numerical simulations, and parametric studies of several simulation parameters were carried out. Flow field features and trajectories of the vortex paths were compared with the experiments for different filling curves, with reasonable agreement. However, because shear stress discontinuities occurred in the predictions a strict volume-defined analytical model was constructed for wall movement with smooth spatial and temporal behaviour reproducing experimental filling curves. Numerical predictions showed not only an improvement in the qualitative features of the flow compared with the experiments, but also a quantitative improvement in the prediction of the vortex core paths. Also the shear stress discontinuities were no longer evident. In order to be able to estimate residence times, instantaneous streamlines and particle tracks were produced. Analysis of shear stresses in the fluid and generation of particle pathlines for residence calculation in 3-D geometries will be carried out in the next feature for model candidates for the final SMV design. Some of the material published during the course of the project is included in APPENDIX 1. In this thesis, attention is paid to the SMV fluid dynamics. However, SMV behaviour is a coupled fluid-solid problem. Future work will be carried out in the muscle modelling. To this end, a careful review has been carried out, and is included in the thesis. Implications for future work are also discussed.

The intensive care unit treats the most critically ill patients in the hospital, and as such the clinical staff in the intensive care unit have to deal with complex, time-sensitive and life-critical situations. Commonly, patients present with multiple organ dysfunctions, require breathing and cardiovascular support, which make diagnosis and treatment even more challenging. As a result, clinical staff are faced with processing large quantities of often confusing information, and have to rely on experience and trial and error. This occurs despite the wealth of cardiovascular metrics that are available to the clinician. Computer models of the cardiovascular system can help enormously in an intensive care setting, as they can take the monitored data, and aggregate it in such a way as to present a clear and understandable picture of the cardiovascular system. With additional help that such systems can provide, diagnosis can be more accurate and arrived at faster, alone with better optimised treatment that can start sooner, all of which results in decreased mortality, length of stay and cost. This thesis presents a model of the cardiovascular system, which mimics a specific patient’s cardiovascular state, based on only metrics that are commonly measured in an intensive care setting. This intentional limitation gives rise to additional complexities and challenges in identifying the model, but do not stand in the way of achieving a model that can represent and track all the important cardiovascular dynamics of a specific patient. One important complication that comes from limiting the data set is need for an estimation for the ventricular time-varying elastance waveform. This waveform is central to the dynamics of the cardiovascular model and is far too invasive to measure in an intensive care setting. This thesis thus goes on to present a method in which the value-normalised ventricular time-varying elastance is estimated from only metrics which are commonly available in an intensive care setting. Both the left and the right ventricular time-varying elastance are estimated with good accuracy, capturing both the shape and timing through the progress of pulmonary embolism and septic shock. For pulmonary embolism, with the algorithm built from septic shock data, a time-varying elastance waveform with median error of 1.26% and 2.52% results for the left and right ventricles respectively. For septic shock, with the algorithm built from pulmonary embolism data, a time-varying elastance waveform with median error of 2.54% and 2.90% results for the left and right ventricles respectively. These results give confidence that the method will generalise to a wider set of cardiovascular dysfunctions. Furthermore, once the ventricular time-varying elastance is known, or estimated to a adequate degree of accuracy, the time-varying elastance can be used in its own right to access valuable information about the state of the cardiovascular system. Due to the centrality and energetic nature of the time-varying elastance waveform, much of the state of the cardiovascular system can be found within the waveform itself. In this manner this thesis presents three important metrics which can help a clinician distinguish between, and track the progress of, the cardiovascular dysfunctions of pulmonary embolism and septic shock, from estimations based of the monitored pressure waveforms. With these three metrics, a clinician can increase or decrease their probabilistic measure of pulmonary embolism and septic shock.

Cardiovascular diseases are the leading cause of death worldwide, and are estimated to kill over 17 million people each year, about 31% of all deaths. In the clinic, the first diagnostic procedure for a suspected cardiac abnormality is often acquisition of an electrocardiogram (ECG), which measures the electrical potential of the heart at the body surface. Understanding the mechanisms underlying generation of the ECG waveforms is crucial for optimal clinical benefit. Computer simulations possess several strengths as a tool to gain this understanding, particularly in terms of human-specificity, flexibility, repeatability, and ethics. The ventricles make up the majority of the cardiac volume and are therefore responsible for the majority of ECG waveforms. Ventricular disorders are the most life-threatening, because the ventricles are responsible for pumping blood to the body. Due to their size it has only recently become possible to perform biophysically detailed simulations of the ventricles and torso using supercomputers. In this thesis, multiscale, mathematical models of the ventricles and torso using the Chaste software library are simulated on high performance computing systems. A description is included of the performance enhancements made in Chaste to improve resource efficiency and accelerate job turnaround, particularly in data storage and the auxiliary tasks of post-processing and data conversion. A novel model of ventricular activation is presented and parametrized using multi-modal human data, and successfully used to simulate normal and pathological QRS complexes. Similarly, repolarization gradients are imposed based on the literature and result in a variety of T waves. Finally, the developed human whole-ventricular and torso models are utilized to gain new insights into possible ionic mechanisms underlying the clinical manifestations of the early repolarization syndrome. Overall, this thesis presents a novel framework for simulation of the human ECG using high performance computers, with possible applications in basic science and computational medicine.

INTRODUÇÃO: O objetivo desta pesquisa foi medir, através da endoscopia, o plexo corióideo no forame interventricular e estruturas no assoalho do terceiro ventrículo, bem como a distância entre as artérias comunicantes posteriores e comparar essas variáveis. MÉTODOS: Estudo observacional, prospectivo realizado em 37 cérebros de cadáveres humanos adultos, de ambos os sexos, no Serviço de Verificação de Óbitos da Universidade de São Paulo, em abril de 2008, utilizando neuroendoscópio rígido. As imagens endoscópicas foram gravadas, corrigidas para distorção e mensuradas. A medida macroscópica entre as artérias comunicantes posteriores foi realizada após o estudo endoscópico. RESULTADOS: As medidas do plexo corióideo no forame interventricular, a distância látero-lateral dos corpos mamilares, a distância do recesso do infundíbulo até os corpos mamilares e do triângulo de segurança no túber cinéreo foram 1,71 mm (±0,77 mm), 2,23 mm (±0,74 mm), 3,22 mm (±0,82 mm), 3,69 mm2 (±2,09 mm2), respectivamente. O aspecto do assoalho do terceiro ventrículo e a distância interna dos corpos mamilares foi 84% opaco e 89% ausente, respectivamente. A distância média entre as artérias comunicantes posteriores foi de 12,5 mm (±2,3 mm). Associações entre translucidez do assoalho do terceiro ventrículo com as seguintes variáveis: distância láterolateral e distância interna dos corpos mamilares, assim como idade, foram identificadas. CONCLUSÕES: Até esta pesquisa, não existiam medidas sobre o plexo corióideo no forame interventricular e distância entre as artérias comunicantes posteriores na região dos corpos mamilares. As variáveis restantes, quando comparadas com a literatura, foram em maior número e em cérebros normais
INTRODUCTION: the objective of this research was to measure, through endoscopy, the interventricular foramen choroid plexus and the third ventricle floor structures, as well the distance between the communicating posterior arteries and compare these variables. METHODS: an observational, prospective study was conducted in 37 brains of adult human cadavers, of both sexes at the Death Check Unit of the University of São Paulo, in April 2008 by means of the rigid neuroendoscope. The endoscopic images were recorded, corrected for distortion and measured. The macroscopic measure between the communicating posterior arteries was performed after the endoscopic study. RESULTS: The measures of the interventricular foramen choroid plexus, the latero-lateral distance of mammillary bodies, the distance from the infundibular recess to the mammillary bodies, safety triangle in the tuber cinereum were 1.71 mm (±0.77 mm), 2.23 mm (±0.74 mm), 3.22 mm (±0.82 mm), 3.69 mm2 (±2.09 mm2), respectively. The aspect of the third ventricle floor and the internal distance of the mammillary bodies was 84% opaque and 89% absent, respectively. The mean distance between the communicating posterior arteries was 12.5 mm (±2.3 mm). Associations between the translucent floor of the third ventricle with the following variables: latero-lateral distance and internal distance of the mammillary bodies, as well as age were identified. CONCLUSIONS: Up this research, there was no account on the measures of the interventricular foramen choroid plexus and the distance between communicating posterior arteries at the level of the mammillary bodies. The remaining variables were in greater number and in normal brains, as compared with the literature

La fraction d'éjection du ventricule droit (FEVD) est un marqueur de survie en cas d'hypertension pulmonaire (PH), mais sa mesure est compliquée et fastidieuse. Le TAPSE (Tricuspid Annular Plane Systolic Excursion) est un bon indice de la FEVD mais il ne mesure que la composante longitudinale de la contraction ventriculaire droite. La fraction de variation surfacique du ventricule droit RVFAC (Right Ventricular Fractional Area Change) semble être un meilleur indice de FEVD car il prend en compte le sens longitudinal et transversal des éléments de la contraction du ventricule droit. Le but de notre étude était d'évaluer la performance RVFAC fonction de la sévérité hémodynamique chez les deux groupes de patients atteints de PH:l'hypertension artérielle pulmonaire (HAP) et l'hypertension pulmonaire thromboembolique chronique (CTEPH).Methodes: Soixante-deux patients atteints d'HTAP et CTEPH ont bénéficié d’un cathétérisme cardiaque droit et d’une IRM cardiaque dans un délai de 72 heures. Les surfaces ventriculaires droite et gauche a la fin de la diastole (RVEDA, LVEDA), la surface du ventricule droit a la fin da la systole (RVESA) et TAPSE ont été mesurés dans la vue quatre cavités. Le RVFAC (RVFAC=RVEDA-RVESA/RVEDA) et le rapport RVEDA/LVEDA ont été calculés. Le diamètre entre la paroi libre et le septum (DF-S) et le diamètre entre les parois antérieure et postérieures du ventricule gauche (DA-P) ont été mesurés et l'indice d’excentricité LV (IE) a été calculé (= DA-P / DF-S). Le RVEF a été calculée à l'aide de coupes jointives de 6 mm en petit axe du ventricule droit.Résultats: La population avait un âge moyen de 58 ans avec une majorité des femmes, la plupart des patients étaient en classe fonctionnelle III, 23 avaient des HAP) et 39 des CTEPH. La RVEF était faiblement corrélée aux variables hémodynamiques de la post-charge et de la fonction VD. Le RVFAC était plus fortement corrélée à FEVD (R2 = 0,65, p <0,001) que TAPSE (R2 = 0,35, p <0,001). Une FEVD <35% était mieux prédite par un RVFAC bas que par une diminution de TAPSE (TAPSE: AUC 0,73 et RVFAC: AUC 0,93, p = 0,0065). Nous avons divisé la population par la médiane de la résistance artérielle pulmonaire (RAP) et nous avons observé que dans le groupe avec la pire sévérité hémodynamique, cette différence a augmenté: dans le groupe avec PVR < 8,5 UW (RVFAC: R2 = 0,66, p <0,001 et TAPSE: R2 = 0,30, p =0,002) et dans le groupe avec PVR > 8,5 UW (RVFAC: R2 = 0,51, p <0,001 et TAPSE: R2 = 0,14, p = 0,041). Le groupe avec PVR> 8,5 WU avait un rapport RVEDA/LVEDA augmenté et une augmentation de l`indice excentricité. Les relations RVEF-RVFAC n’étaient pas différentes entre les groupes de HAP et CETPH.Conclusion: La fraction de variation surfacique du ventricule droit RVFAC fournit un reflet simple et fiable de la FEVD peut-être parce que contrairement à TAPSE qui ne prend en compte que le raccourcissement longitudinal, RFVAC prend également en compte la composante transversale de la fonction ventriculaire droite
The right ventricular ejection fraction (RVEF) is a surrogate marker in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The TAPSE (Tricuspid Annular Plane Systolic Excursion) is a good index of RVEF, though it measures only the longitudinal component of right ventricular contraction. The RVFAC (Right Ventricular Fractional Area Change) seems to be a better index of RVEF because it takes into account the longitudinal and the transversal components of right ventricular contraction. The aim of our study was to evaluate the RVFAC performance according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolicpulmonary hypertension (CTEPH).Methos: Sixty-two patients with PAH and CTEPH underwent right heart catheterization and cardiac MR in a 72-hour delay. The right and left ventricle end diastolic areas (RVEDA, LVEDA), the right ventricle end systolic area (RVESA) and TAPSE were measured in the four chamber view. The RVFAC (RVFAC=RVEDA–RVESA/RVEDA) and the RVEDA/LVEDA relationship werecalculated. The diameter between the left ventricle (LV) free wall and the septum (dL-S) and the diameter between the anterior and posterior walls (dAP) were measured and the LV eccentricity index (EI) was calculated (EI=dAP/dL-S). The RVEF was calculated by using 6 mm RV short axis cines.Results: The population had mean age of 58 years with female majority, most of the patients were in functional class III, 23 had pulmonary arterial hypertension (PAH) and 39 had chronic thromboembolic pulmonary hypertension (CTEPH). The RVEF was weakly correlated to the hemodynamic variables of RV afterload and function. The RVFAC was morestrongly correlated to RVEF (R2=0.65, p<0.001) than TAPSE (R2=0.35, p<0.001). RVEF<35% was better predicted by RVFAC than TAPSE (TAPSE: AUC 0.73 and RVFAC: AUC 0.93, p=0.0065). We divided the population by the median of the pulmonary vascular resistance (PVR) and we observed that in the group with worse hemodynamic severity this difference increased: inthe group with PVR<8,5WU (RVFAC: R2=0.66, p<0.001 and TAPSE: R2=0.30, p=0.002) and in the group with PVR>8,5 WU (RVFAC: R2=0.51, p<0.001 and TAPSE: R2=0.14, p=0.041). The group with PVR>8,5WU had an increased RVEDA/LVEDA and an increased EI. There was no differences in the RVEF relationships between the groups of PAH and CETPH.Conclusion: The RVFAC was better correlated to RVEF than TAPSE in the groups with less severe and more severe hemodynamics. In patients with increased hemodynamic severity, with no difference in the performance in theHAP or CTEPH groups. RVFAC was a better index of RVEF possibly because it takes into account the transversal component of right ventricular function

Orientadores: Jose Wilson Magalhães Bassani, Rosana Almada Bassani
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação
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Resumo: A desfibrilação é a única terapia conhecida para reverter o quadro de fibrilação ventricular. Entretanto, a estimulação do coração com campos elétricos de grande magnitude durante a desfibrilação pode lesar miócitos cardíacos, e, como conseqüência, a eficiência contrátil do coração ser reduzida. Neste trabalho, estudamos o efeito da estimulação por campo elétrico (E) de alta intensidade sobre miócitos cardíacos isolados de rato. O valor máximo de potencial extracelular gerado por E (Ve-max) foi estimado usando-se um modelo eletromagnético. Os principais resultados foram: a) A aplicação de E de alta intensidade causa aumento sustentado de [Ca2+] citoplasmática ([Ca2+ ]i), bem como contratura, que são dependentes de [Ca2+] extracelular; para campos maiores que 50 V/cm, estas respostas são irreversíveis e levam à morte celular; b) retículo sarcoplásmatico, mitocôndrias, trocador Na+-Ca2+ de canais de Ca2+ do sarcolema não contribuem de forma significativa para estes efeitos; c) durante aplicação de choques a células despolarizadas com alta [K+] extracelular, observou-se um incremento de Ve-max semelhante ao valor do potencial transmembrana de repouso (Vm ~-85 mV), o que indica que Ve-max pode ser considerado uma estimativa razoável da máxima variação de Vm durante o choque; d) aumento da resistência celular ao efeito letal de E, avaliada pelo valor de E associado a probabilidade de letalidade de 50% (EL50), ocorreu com a aplicação de pulsos bipolares da mesma energia, durante a estimulação de receptores ß- adrenérgicos, e em miócitos isolados de animais nos quais foi induzido stress por imobilização e choques nas patas repetidos. Conclui-se que: a) O aumento sustentado de [Ca2+]i ocorre provavelmente por influxo do íon através de poros hidrofílicos formados na membrana devido à imposição de E de alta intensidade (eletroporação); b) a superioridade de pulsos desfibrilatórios bipolares, já descrita na literatura, pode dever-se, pelo menos em parte, pelo menor potencial letal desta forma de onda; c) tanto a estimulação ß-adrenérgica in vitro, quanto a condição de stress parecem conferir proteção contra o efeito letal de E. Espera-se que estes resultados representem uma contribuição para o desenvolvimento de procedimentos mais seguros, tanto para desfibrilação, quanto para estimulação marca-passo do coração
Abstract: Electric defibrillation is currently the treatment able to reverse ventricular fibrillation. However, cardiac stimulation with high-intensity electric fields may cause injury to myocardial cells, thus impairing cardiac contractility. In this study, the effects of highintensity electric fields (E) on isolated rat ventricular myocytes were analyzed. The maximum value of field-induced extracellular potential (Ve-max) was estimated using an electromagnetic model. Our main results were: a) Application of high-intensity E causes sustained increase in cytosolic [Ca2+] ([Ca2+]i) and marked cell contracture, and both effects depend on the presence of extracellular Ca2+; for E> 50 V/cm, these responses are irreversible and lethal injury develops; b) sarcoplasmic reticulum, mitochondria, Na+-Ca2+ exchanger and sarcolemmal L-type Ca2+ channels do not seem to contribute significantly to such effects; c) when shocks were applied to cells depolarized by high extracellular [K+], Ve-max was increased by an extent that was close to the value of the resting transmembrane potential (Vm ~-85 mV), which indicates that Ve-max may be considered a reasonable estimation of the maximum variation of Vm during the shock; d) increase in cell resistance to the lethal effect of E, assessed as the value of E associated to 50% probability of lethality (EL50), was observed during application of biphasic stimuli with the same pulse energy, during ß-adrenergic receptor stimulation, and in myocytes isolated from rats in which stress was induced by repeated immobilization and footshock. It may be concluded that: a) The sustained increase in [Ca2+]i is probably due to Ca2+ influx through hydrophilic membrane pores generated during application of high-intensity E (electroporation); b) the better defibrillation results described in the literature with biphasic shock may be due, at least partly, to the lesser ability of this waveform to cause lethal injury; c) both in vitro ß-adrenergic stimulation and the stress condition in vivo appear to exert a protective effect against the lethal effect of E. We expect that the present results may contribute to the development of safer procedures for both pacemaker and defibrillatory field stimulation of the myocardium
Doutorado
Engenharia Biomedica
Doutor em Engenharia Elétrica

The morbidity of and the mortality from cardiac disease are higher in diabetic patients. Clinical and experimental evidence suggests that diabetes-induced changes at the level of myocardium can, at least partially, contribute to these cardiac problems. The mechanism(s) involved in this diabetic cardiomyopathy is still unclear, but one defect appears to occur in the alpha₁-adrenoceptor system. Altered myocardial sensitivity and responsiveness to alpha₁-adrenoceptor agonists have been reported in experimental diabetes mellitus. Stimulation of alpha₁-adrenoceptors is known to produce a positive inotropic effect and has been recently shown to stimulate the hydrolysis of phosphoinositides. To evaluate the possibility that the changes in the inotropic responsiveness to alpha₁-adrenoceptor stimulation in the diabetic heart could be linked to altered alpha₁-adrenoceptor-stimulated phosphoinositide turnover and further to the development of diabetic cardiomyopathy, we studied contractility and receptor-stimulated phosphoinositide turnover following norepinephrine (in the presence of propranolol) stimulation in right ventricles from male Wistar rats (200-225 g) which were made diabetic with streptozotocin (55 mg/kg, i.v.). Rats were sacrificed six weeks after the induction of diabetes. Diabetic rats were characterized by decreased body weight gain, hypoinsulinemia, hyperglycemia and hyperlipidemia. Stimulation of alpha₁-adrenoceptors by norepinephrine (in the presence of propranolol) in right ventricles resulted in the formation of inositol monophosphate (measured with a radioisotope method) and inositol 1,4,5-trisphosphate (measured with an inositol 1,4,5-trisphosphate protein binding assay kit) in a time- and concentration-dependent manner in both control and diabetic rats. The increase in inositol 1,4,5-trisphosphate levels preceded the increase in the alpha₁-adrenoceptor-mediated positive inotropic effect. Diabetic hearts showed a greater maximum inotropic response to norepinephrine stimulation and also had a higher inositol 1,4,5-trisphosphate levels. However, with the radioisotope method, a decreased inositol monophosphate formation was shown in diabetic hearts compared with controls. Omega-3 fatty acids supplementation (Promega[symbol omitted], 0.5 ml/kg/day) had no significant effect on the changes in norepinephrine-stimulated inositol monophosphate formation in diabetic hearts. In the presence of the cyclooxygenase inhibitor indomethacin or the thromboxane synthetase inhibitor imidazole, the norepinephrine-stimulated positive inotropic effect and inositol 1,4,5-trisphosphate formation were significantly increased in control hearts, but were unaltered in the hearts from diabetics. The addition of the prostacyclin synthetase inhibitor tranylcypromine reduced the norepinephrine-stimulated positive inotropic effect and inositol 1,4,5-trisphosphate formation only in diabetic hearts and had no effect in the controls. While inositol 1,4,5-trisphosphate may be able to mediate only transient inotropic effects produced by alpha₁-adrenoceptor stimulation, diacylglycerol may provoke a sustained positive inotropic effect by activating slow Ca²⁺ channels through stimulation of protein kinase C. Our results showed that the diabetic hearts had a higher protein kinase C activity in the membrane fraction compared with controls and this was accompanied by a decrease in cytosolic protein kinase C activity. The present study suggests that the increases in inositol 1,4,5-trisphosphate levels and the membrane fraction protein kinase C activity may be implicated in the increased inotropic responsiveness to alpha₁-adrenoceptor stimulation in the hearts of the streptozotocin-diabetic rats. The increases in inositol 1,4,5-trisphosphate level and protein kinase C activity could induce Ca²⁺ overload in the diabetic heart which might be involved in the development of diabetic cardiomyopathy. The results from the omega-3 fatty acid study indicate that the changes in cardiac alpha₁-adrenoceptor-mediated inositol phosphates formation cannot contribute to the previously described improved cardiac function of omega-3 fatty acid-treated streptozotocin-diabetic rats. The nature and physiological significance of the enhanced positive inotropic effect and inositol 1,4,5-trisphosphate formation in the control heart with the addition of indomethacin and imidazole is still unclear. The effect of tranylcypromine may indicate the participation of prostaglandins in mediating the enhanced alpha₁-inotropic effect of norepinephrine in the diabetic heart.
Pharmaceutical Sciences, Faculty of
Graduate

Includes bibliographical references (leaves 52-56).
The expanding application of cardiac resynchronization (CRT) and implantable cardioverter-defibrillator therapy (lCD) to include patients with congenital heart disease requires careful evaluation of selection criteria and unconventional adaptive strategies to ensure clinical efficacy. A single centre prospective analysis of adults post atrial redirection surgery (Mustard operation) for dextro-transposition of the great arteries (d-TGA) presenting with systemic right ventricular (sRV) dysfunction and at risk of sudden cardiac death (SCD). All patients ( mean age 25 years, range 18-35) with varying functional disability{New York Heart Association (NYHA) II-III} receiving ICDs ± concomitant CRT were evaluated. Total follow-up period was 24 months. A patient individualized approach was used for device implantation. Endocardial, epicardial and transthoracic defibrillation strategies were examined in 5 consecutive cases. A hybridized form of CRT was employed in two patients. Only one patient demonstrated response to therapy while the other deteriorated during biventricular pacing (BVP). This prompted a novel approach to CRT using noncontact mapping (NCM) and acute intra-arterial blood pressure response to guide endocardialsRV lead placement in a single patient. The ejection fraction increased from 23 -33% within 1week post procedure and clinical improvement was sustained after 6-months follow-up. Application of CRT II CD therapy to patients with sRV dysfunction requires individualized and adaptive strategies to overcome anatomical constraints. This study represents a chronological and evolutionary account of these measures.

Hypothermia alters myocardial electrophysiology and can result in ventricular arrhythmias. Therapeutic hypothermia is used to mitigate neurological injury after cardiac arrest with moderate hypothermia (32-340C) to minimise the risk ventricular arrhythmias. The mechanisms responsible remain poorly understood and we thus sought to examine the arrhythmogenicity of hypothermia in a large animal model. Ten sheep were cooled systemically using an extracorporeal circuit. Surface 12 lead ECGs, and epicardial and transmural potentials (N=220) were recorded. Potentials were recorded during sinus rhythm (SR) and ventricular pacing (VP). Local activation time (AT), recovery time (RT), and corrected activation-recovery intervals (ARIc) were measured. Hypothermia resulted in a prolonged AT, RT and ARIc during SR/VP. Local AT, RT and ARIc heterogeneity was increased particularly during VP. The main increase in heterogeneity during SR occurred between normothermia and 340C. Depolarisation of the lateral LV wall was significantly more affected by hypothermia. Hypothermia resulted in ST elevation predominantly over the infero-basal region of the heart and was associated with localised slowing of depolarisation and more rapid depolarisation. Hypothermia was not more arrhythmogenic at 300C compared with 340C during SR which may support deeper hypothermia in post cardiac arrest situations.

La dysfonction ventriculaire gauche reste sous-diagnostiquée en pratique clinique actuelle car les paramètres conventionnels d’échographie ne sont pas suffisamment sensibles pour détecter des modifications fines de la fonction cardiaque. L’introduction récente de l’échocardiographie de suivi des marqueurs acoustiques (speckle tracking echocardiography) a permis par ses capacités descriptives de la mécanique cardiaque, de revisiter la contraction cardiaque et, de ce fait, de proposer une nouvelle approche échographique de l’évaluation de la fonction ventriculaire gauche.

A travers trois études, nous avons montré que l’analyse des indices de déformation permet d’objectiver des modifications de fonction ventriculaire gauche indétectables en échocardiographie conventionnelle dans des situations complexes à fraction d’éjection conservée, en dépit de l’augmentation modérée de la fréquence cardiaque qui leur est associée. Les situations que nous avons étudiées sont les suivantes :l’adaptation physiologique à l’hypoxie au niveau de la mer et en altitude, et les situations pathologiques que sont le syndrome de mal d’altitude chronique, et la cardiomyopathie associée à l’ataxie de Friedreich.

L’intégration de nos résultats et des informations disponibles dans la littérature permet de suggérer que l’utilisation de toutes les ressources offertes par l’échocardiographie de suivi des marqueurs acoustiques permet d’améliorer l’évaluation de la fonction cardiaque au-delà de la fraction d’éjection, en offrant une meilleure identification de situations pathologiques mais également une meilleure compréhension de situations physiologiques et pathologiques.

L’utilisation généralisée des indices de déformation pour l’évaluation de la fonction ventriculaire gauche en pratique clinique connaît néanmoins d’importantes limitations que nous abordons dans la discussion de ce travail. Au terme d’investigations complémentaires et de standardisation de la technique, l’incorporation d’un algorithme d’évaluation échographique de la fonction cardiaque à FEVG conservée combinant les paramètres échographiques conventionnels et les indices de déformation pourra être évalué de façon prospective pour sa translation en pratique clinique, avec pour finalité la proposition d’une définition mieux adaptée de l’insuffisance cardiaque à FEVG conservée.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished

Orientadores: Carlos Kenichi Suzuki, Aron José Pazin de Andrade
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Mecânica
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Resumo: Neste trabalho, foi realizado um estudo experimental de uma Bomba de Sangue Ápice Ventricular (BSAV) para sua análise como um dispositivo de assistência ventricular. Este estudo faz parte do desenvolvimento desta bomba e serviu como fundamentação na evolução do projeto. A BSAV é uma bomba de sangue centrífuga de fluxo contínuo, para ser utilizada como dispositivo de assistência ventricular em pacientes com doenças cardíacas crônicas. Foi realizado um estudo de posicionamento anatômico, onde a bomba foi implantada em um coração de um porco e não foram encontrados indícios de possíveis danos aos tecidos e órgãos circunvizinhos. Em seguida, foi feito um ensaio experimental, onde foi comparado o desempenho de protótipos com características distintas, visando sua otimização em relação ao desempenho hidrodinâmico. Também foi realizado um estudo para avaliação do trauma as células do sangue causado pela ação da bomba, no qual os resultados mostraram um baixo dano as células. A seguir, foi feito estudo com um protótipo conectado em um simulador cardiovascular híbrido (matemático e físico), onde este protótipo às condições simuladas de um sistema cardiovascular com insuficiência cardíaca. Com a BSAV conectada ao sistema obteve-se, uma melhora no fluxo de sangue, frequência cardíaca e pressão aórtica. Os resultados indicam que a BSAV é adequada para aplicação como dispositivo de assistência ventricular esquerda e é uma alternativa promissora no tratamento de pacientes com doenças cardíacas crônicas
Abstract: In this work an experimental study was realized with the Apico-Ventricular Blood Pump (AVBP) used as a ventricular assist device. This study is part of the device's development and the results were used for project evaluation and improvement. AVBP is a continuous flow centrifugal blood pump for ventricular assistance in chronic cardiac patients. Initially, an anatomic study was performed, in this study an AVBP prototype was implanted in a corpse of a pig, the clinical staff appointed, none damage to the nearby tissues and organs due to the contact with the device. Following step consists in an experimental hydrodynamic performance test. For this test the prototypes used had distinct specific construction characteristics variations among themselves, for device optimization, the performance of these different prototypes were compared, and the prototypes which presented a better performance had their characteristic adopted in the project. A study to determine the traumatic effect of the pump on blood cells was conducted, the results showed low damage to the blood cells. A hybrid mock loop circulation system (mathematical and physic) where the pump, was connected to a system with heart disease, was used. When the AVBP was inserted in the system, cardiac output, heart rate and aortic pressure went to normal values. All results indicated the performance of the AVBP as ventricular assist device, an alternative for treatment of patients with cardiac chronic diseases
Mestrado
Materiais e Processos de Fabricação
Mestre em Engenharia Mecânica

The projects of this thesis examine the complex interaction between isotonic exercise, functional capacity, exercise-induced myocardial ischaemia, severity of regurgitation and left ventricular function in patients with significant chronic mitral regurgitation. The concept of left ventricular contractile reserve, i.e. the ability of the left ventricle to increase its contractility and decrease its end systolic volume with isotonic exercise, is explored. In patients with chronic isolated mitral regurgitation without coronary disease, isotonic exercise was associated with a slight decrease in left ventricular end diastolic volume but a marked decrease in end systolic volume, resulting in a significant increase in the stroke volume and ejection fraction. Early after uncomplicated mitral valve repair surgery, there was a significant decrease in the left ventricular ejection fraction with a proportion of the patients developing left ventricular dysfunction despite a normal pre-operative ejection fraction. When different pre-operative echocardiographic indices of left ventricular function were evaluated for their ability to predict left ventricular function after mitral valve repair, the exercise indices were found to be superior to resting indices. Left ventricular end systolic volume immediately after exercise was found to be the best predictor. The optimal cut-off was at 25 ml/m2, which had a sensitivity and specificity of 83% in predicting early post-operative left ventricular dysfunction. Exercise indices appeared to be superior to resting indices in identifying patients with persistent left ventricular dysfunction <1 year after mitral valve repair. The concept of contractile reserve was further examined by estimating the left ventricular stroke work from simplified pressure-volume loops, which were constructed from non-invasively obtained parameters with geometric assumptions. Left ventricular stroke work immediately after exercise, but not at rest, was found to be significantly lower in patients with latent left ventricular dysfunction. Patients without latent ventricular dysfunction had similar increases in stroke work with exercise compared with healthy normal subjects. The ability of the left ventricle to increase its stroke work with exercise, a measure of the contractile reserve, was correlated with the left ventricular ejection fraction after mitral valve repair. A numerical model was constructed using the clinical data as input parameters. The results from the numerical model were similar to that obtained from the clinical study, testifying that the observation made in the clinical study was valid and independent of the geometric assumptions made in constructing the simplified pressure-volume loops. Left ventricular pressure-volume loops under different loading conditions were plotted from simultaneously measured left ventricular pressure and volume to measure the left ventricular end systolic elastance (Ees) and preload recruitable stroke work relationship (MSW). Despite normal or near normal haemodynamics at rest, a significant proportion of the study patients were found to have impaired left ventricular contractility, as measured by Ees, consistent with a state of latent left ventricular dysfunction. Exercise indices of left ventricular function were better correlated with Ees and MSW than resting indices. There were highly significant inverse relationships between end systolic volume index immediately after exercise and Ees and MSW. Moreover, there was a significant powered relationship between MSW and exercise left ventricular ejection fraction. There was no such relationship between Ees or MSW and any of the resting echocardiographic indices of left ventricular function. Furthermore, the optimal diagnostic cut-off level of end systolic volume index after exercise at 25 ml/m2 accurately identified those with impaired left ventricular contractility as defined by an Ees of > 2 mmHg/ml. In patients with chronic organic mitral regurgitation with ejection fraction of < 50%, objectively measured functional capacity, VO2max, was correlated with exercise cardiac output, patient age and gender but not to the severity of the mitral regurgitation or the resting left ventricular function. The VO2max of these patients were significantly lower than that of age and gender-matched healthy controls despite these patients' relative lack of subjective symptoms. There were significant individual variations in the response of the severity of the mitral regurgitation to isotonic exercise. Patients whose regurgitant stroke volume increased had a lower exercise cardiac output than those whose regurgitant stroke volume decreased. Such variability was also seen with the response of the left ventricular function to exercise. Patients whose left ventricular end systolic volume increased with exercise, i.e. patients with a limited contractile reserve, had a lower exercise cardiac output and lower VO2max than those whose end systolic volume decreased with exercise. The determinants of exercise capacity were then examined in patients with functional mitral regurgitation and left ventricular dysfunction. VO2max of these patients was correlated with exercise cardiac output and exercise left ventricular ejection fraction, a situation similar to that seen in patients with organic mitral regurgitation and normal left ventricular function. Furthermore, indices of left ventricular systolic function at rest and pulsed wave Doppler indices of diastolic function showed no significant correlations with VO2max. The determinants of VO2max remained unchanged in these patients after four weeks of supervised exercise training. The four weeks of exercise training resulted in a significant decrease in left ventricular end systolic volume, a trend towards an increase in left ventricular ejection fraction and some restoration of the contractile reserve. The total exercise time almost doubled. However, this dramatic improvement in total exercise time was accompanied only by non-significant increases in VO2max and left ventricular ejection fraction. Therefore, the benefits of exercise training in these patients may involve more than just central mechanisms. Exercise induced myocardial ischaemia may also contribute to a limited left ventricular contractile reserve in patients with mitral regurgitation. Electrocardiographic changes at rest are commonly seen in patients with mitral regurgitation due to mitral valve prolapse. These resting electrocardiographic changes make exercise electrocardiography uninterpretable for exercise-induced ischaemia. Exercise electrocardiographic changes are also commonly encountered in these patients despite the absence of coronary artery disease and a normal resting electrocardiogram, making exercise electrocardiography unreliable as a non-invasive screening test for coronary artery disease. In these patients, exercise echocardiography was slightly more sensitive but significantly more specific in diagnosing significant coronary artery disease. The overall accuracy and the positive predictive value were significantly higher for exercise echocardiography than for exercise electrocardiography. The "cost-effectiveness" of different diagnostic strategies for coronary artery disease in patients with mitral valve prolapse was examined based on the results of the clinical study. Strategies involving exercise electrocardiography as part of the screening test were costly and were associated with a high false negative rate. Strategies involving exercise echocardiography were more accurate and less costly but the initial costs of exercise echocardiography for all patients meant that the overall costs were still considerable. Assessing the pre-test probability of coronary artery disease in these patients and using exercise echocardiography as the initial test for patients with at least a moderate pre-test probability of coronary artery disease seemed to result in the best compromise between cost and effectiveness. The studies of this thesis have shown that a limited cardiac contractile reserve is a sign of latent ventricular dysfunction in patients with chronic mitral regurgitation. The presence of a limited contractile reserve can be used to predict left ventricular dysfunction after mitral valve repair. The concept of a limited contractile reserve is further supported by the finding of a limited increase in left ventricular stroke work with exercise from a theoretical as well as a numerical model of left ventricular pressure-volume loops. Exercise echocardiographic indices show better correlations to invasively measured Ees and MSW than resting indices. VO2max in these patients is determined more by their ability to increase their forward cardiac output with exercise and not by the regurgitant volumes. Exercise training in patients with left ventricular dysfunction and functional mitral regurgitation results in some restoration of contractile reserve. Exercise echocardiography is also a reliable and cost-effective test in the non-invasive screening for coronary artery disease in these patients. Based on the results of the studies in the thesis, one can incorporate exercise echocardiography as one of the important assessment tools in the management of patients with significant mitral regurgitation as it allows measurement of left ventricular volumes and assessment of contractile reserve. Further studies are needed to examine whether a policy of monitoring of contractile reserve in these patients to guide therapy and surgical referral will result in a better preservation of long term left ventricular function, an improvement in functional capacity and patient outcome.

This study used an in situ heart preparation to analyze the power and work of spontaneously beating hearts of four anurans (R. marina, L. catesbeianus, X. laevis, P. edulis) and three urodeles (N. maculosus, A. tigrinum, A. tridactylum) in order to elucidate the meaning of relative ventricle mass (RVM) in terms of specific cardiac performance variables. This study also tests two hypotheses: 1) the ventricles of terrestrial species (R. marina, P. edulis, A. tigrinum) of amphibians are capable of greater maximum power outputs (Pmax) compared to aquatic species (X. laevis, A. tridactylum, N. maculosus, L. catesbeianus) and, 2) the ventricles of Anuran species (R. marina, P. edulis, L. catesbeianus, X. laevis) are capable of greater maximum power output compared to aquatic species (A. tigrinum, A. tridactylum, N. maculosus). The data supported both hypotheses. RVM was significantly correlated with Pmax, stroke volume, cardiac output, afterload at Pmax, and preload at Pmax. Preload at Pmax and afterload at Pmax also correlated very closely with each other, suggesting that an increase blood volume and/or increased modulation of sympathetic tone may influence interspecific variation RVM and may have played a role in supporting higher rates of metabolism, as well as dealing with hypovolemic stresses of life on land.

Chronic ventricular sympathectomy elicits changes in the coronary circulation, myocardial oxygen consumption and size of infarction resulting fromcoronary occlusion. These changes indicate a change occurring in the basic metabolism of the heart in response to the removal of its sympathetic nervous input. This hypothesis was tested using two groups of dogs, a shamoperated control and a ventricular sympathectomized group. The sympathectomy procedure was an intrapericardial surgical technique which selectively removes ventricular sympathetic input. Four weeks after surgery, left ventricular tissue samples were obtained and rapidly frozen to -80°C. Selected metabolic variables were then compared between the two groups.

Dissertação de Mestrado Integrado em Medicina Veterinária
É importante ter um conhecimento geral da anatomia cerebral canina de forma a interpretar os resultados obtidos através da TAC, especialmente pelos cães terem grandes variações a nível do formato do crânio pese embora no estudo terem sido consideradas apenas raças de crânio mesocefálico. A medição quantitativa do volume ventricular cerebral foi feita em 50 cães através de tomografia axial computadorizada (TAC), os quais tiveram proveniência da consulta de Neurologia no Hospital Escolar da Faculdade de Medicina Veterinária em Lisboa. A média de idades foi de 9,84 e a mediana de 9. O valor médio para o volume ventricular cerebral lateral direito foi de 463,93mm3, para o volume ventricular cerebral lateral esquerdo de 535,87mm3, para o volume do 3º ventrículo de 110,54mm3 e a média do volume total foi de 1110,50mm3. Dos 50 casos analisados, 31 (62%) tinham o ventrículo cerebral lateral esquerdo mais largo que o direito, 19 (38%).

L'interaction vd-vg a d'abord ete etudiee par une approche geometrique: une methode de quantification du contour endocardique du vg a ete appliquee sur les coupes echocardiographiques dans une population pediatrique normale et dans des cardiopathies congenitales (cc). L'evaluation des distorsions du vg a ete ramenee a un probleme de reconnaissance de formes c'est-a-dire de comparaison avec une echelle de formes. La transformee de fourier permet de caracteriser les contours des formes modelisees et les coefficients permettent de generer un facteur de forme (ff) pour chaque forme etudiee et caracterisee par une transformee. Des correlations lineaires ont ete mises en evidence entre ff et le gradient transseptal dans les cc. Pour tenir compte des facteurs myocardiques mecaniques (epaisseur, organisation des fibres) un modele biomecanique bidimensionnel du vg a ete valide dans un meme type de populations en utilisant les coupes echocardiographiques. Ce modele nous a permis d'etudier l'influence respective des parametres rheologiques et geometriques sur le ff pour differents niveaux du gradient transseptal. Les parametres geometriques sont tous determinants pour ff du vg dans les cc; le modele de cisaillement de la matrice de collagene est un facteur determinant du ff et a permis d'evaluer la dynamique du collagene dans les cc; la tension isometrique maximale est determinee par l'epaisseur et n'est pas reliee a ff. Le gradient transseptal n'est pas le determinant unique du ff du vg; celui-ci est soumis a l'influence de facteurs geometriques et a la rheologie du vg

Abstract Collagen XIII is a type II transmembrane protein, which has a short intracellular domain and a large, mainly collagenous ectodomain. It is located at many cell-matrix junctions and in focal adhesions in cultured cells and it has a function in cell adhesive processes. Overexpression of collagen XIII molecules with an 83 amino acid deletion in part of the ectodomain leads to fetal lethality in Col13a1del transgenic mice. Doppler ultrasonography was performed at 12.5 days of gestation on fetuses resulting from heterozygous matings and matings between heterozygous and wild-type mice. Some fetuses had atrioventricular valve regurgitation (AVVR) and all of them were transgene positive. In addition, fetuses had pathological changes in functional parameters. Histological analysis showed the trabeculation of the ventricles to be reduced and the myocardium to be thinner in the fetuses with AVVR. Based on in situ hybridization (ISH), collagen XIII mRNA are normal constituents of these structures. Overexpression of mutant collagen XIII results in mid-gestation cardiac dysfunction in fetuses, and these disturbances in cardiac function may lead to death in utero. The heterozygous mice that were initially of normal appearance had an increased susceptibility to develop B cell lymphomas, which originated in the mesenteric lymph node. Collagen XIII protein was not detected in normal lymph nodes or in the lymphomas. The incidence of lymphomas was higher in conventional conditions than in a specific pathogen-free facility. In addition, the expression of collagen XIII was localized in the intestine and the basement membrane was highly abnormal. These findings suggest that collagen XIII is a critical determinant of lymphanogenesis. Using ISH, antibody staining and RT-PCR techniques collagen XIII expression was analyzed during carcinogenesis in mice and in man. Collagen XIII expression increased during carcinogenesis in mice and in man. In the malignant process collagen XIII mRNA localized in the basal epithelium and in the invasive cells. According to antibody staining malignant invasive cells were positive. Results may reflect the disturbed adhesion of epithelial cells and ECM and that may affect the behaviour of the malignant cells, suggesting that collagen XIII has a significant role in the initiation of the invasion.

The intracranial system consists of three main basic components - the brain, the blood and the cerebrospinal fluid. The physiological processes of each of these individual components are complex and they are closely related to each other. Understanding them is important to explain the mechanisms behind neurostructural disorders such as hydrocephalus. This research project consists of three interrelated studies, which examine the mechanical properties of the brain at the macroscopic level, the mechanics of the brain during hydrocephalus and the study of fluid hydrodynamics in both the normal and hydrocephalic ventricles. The first of these characterizes the porous properties of the brain tissues. Results from this study show that the elastic modulus of the white matter is approximately 350Pa. The permeability of the tissue is similar to what has been previously reported in the literature and is of the order of 10-12m4/Ns. Information presented here is useful for the computational modeling of hydrocephalus using finite element analysis. The second study consists of a three dimensional finite element brain model. The mechanical properties of the brain found from the previous studies were used in the construction of this model. Results from this study have implications for mechanics behind the neurological dysfunction as observed in the hydrocephalic patient. Stress fields in the tissues predicted by the model presented in this study closely match the distribution of histological damage, focused in the white matter. The last study models the cerebrospinal fluid hydrodynamics in both the normal and abnormal ventricular system. The models created in this study were used to understand the pressure in the ventricular compartments. In this study, the hydrodynamic changes that occur in the cerebral ventricular system due to restrictions of the fluid flow at different locations of the cerebral aqueduct were determined. Information presented in this study may be important in the design of more effective shunts. The pressure that is associated with the fluid flow in the ventricles is only of the order of a few Pascals. This suggests that large transmantle pressure gradient may not be present in hydrocephalus.

Introdução: A hipertrofia ventricular esquerda é importante fator de risco de morbidade e mortalidade cardiovascular. Sua associação com variantes funcionais do sistema renina-angiotensina é controversa. Objetivos: Avaliar a associação entre massa ventricular esquerda e função sistólica e diastólica do ventrículo esquerdo e os polimorfismos inserção/deleção do gene da enzima de conversão da angiotensina e M235T do gene do angiotensinogênio. Métodos: Estudo observacional realizado numa amostra da população da cidade de Vitória (Espírito Santo), utilizando como base a metodologia do projeto Mônica da Organização Mundial da Saúde. Realizamos avaliação clínica, perfil antropométrico, análise laboratorial e ecocardiograma em 652 indivíduos previamente genotipados para polimorfismos da enzima de conversão da angiotensina e do angiotensinogênio. Analisamos massa ventricular esquerda indexada pela área de superfície corpórea e pela altura2,13. Classificamos o ventrículo esquerdo em padrões geométricos: padrão normal, remodelamento concêntrico, hipertrofia concêntrica e hipertrofia excêntrica. A função sistólica ventricular esquerda foi avaliada pela fração de ejeção medida ao modo unidimensional. A função diastólica foi analisada pelo fluxo mitral (onda E, onda A, relação E/A, tempo de desaceleração e tempo de relaxamento isovolumétrico) e pelo Doppler tecidual (velocidade miocárdica em região próxima ao anel mitral septal e lateral: ondas E e A e relação E/E). Resultados: A média de idade da população estudada foi 51 ± 10 anos sendo 59% dos participantes do sexo feminino e 20,8% obesos. Em nossa amostra, 47% dos indivíduos foram classificados como hipertensos. Não houve associação entre hipertensão arterial e os genótipos analisados. Após análise univariada, não encontramos associação entre os polimorfismos inserção/deleção da enzima de conversão da angiotensina e M235T do angiotensinogênio e índice de massa ventricular esquerda, padrões geométricos do ventrículo esquerdo, função sistólica avaliada pela fração de ejeção e os vários parâmetros de função diastólica analisados.
Introduction: Left ventricular hypertrophy is an important risk factor for cardiovascular morbidity and mortality. Its association with the reninangiotensin system genetic variants is controversial. Objectives: To assess the association between left ventricular mass, left ventricle systolic and diastolic functions, and polymorphisms of the insertion/deletion angiotensin converting enzyme and M235T angiotensinogen genes. Methods: Observational study in adults from Vitoria (Brazil) using the methodology of the Monica project of the World Health Organization. We performed clinical examination, anthropometric assessment, laboratory analysis and transthoracic echocargiography studies in 652 adults who were previously genotyped for polymorphisms of the angiotensin-converting enzyme and angiotensinogen. We measured left ventricular mass indexed to body surface area and height 2,13, left ventricular ejection fraction, and diastolic function using mitral flow and tissue Doppler. Left ventricle was classified into following geometric patterns: normal, concentric remodeling, concentric hypertrophy and eccentric hypertrophy. Left ventricular systolic function was assessed by ejection fraction by analysis of the M-mode echocardiogram. Diastolic function was assessed using mitral flow (E wave, A wave, E/A ratio, deceleration time and isovolumic relaxation time), and Doppler tissue imaging (mitral annulus velocity in septal and lateral region: E` and A` waves, and E/E`ratio). Results: Mean age of the studied population was 51±10 years; 59% of the subjects were women and 20,8% were obese. Forty seven percent of the individuals were classified as hypertensive. Hypertension was not associated with any of the studied genotypes. Univarate analysis showed no correlation between polymorphisms of the insertion/deletion angiotensin-converting enzyme and M235T angiotensinogen gene variants, left ventricular mass index, left ventricular geometric patterns, and systolic and diastolic functions. Taking together these data indicated no evidence for the association of ACE and angiotensinogen gene variants with cardiac mass and function assessed by echocardiography.

Thesis (MSc (Physiological Sciences))--University of Stellenbosch, 2009.
Physiological cardiac hypertrophy is characterized by the heart’s ability to increase mass in a reversible fashion without leading to heart failure. In contrast, pathological cardiac hypertrophy leads to the onset of heart failure. For this study, we investigated a model of physiological hypobaric hypoxia-mediated right ventricular (RV) hypertrophy (RVH). Here our hypothesis was that the hypertrophic response and associated changes triggered in the RV in response to chronic hypobaric hypoxia (CHH) (increased RV mass, function and respiratory capacity) are reversible. To test our hypothesis we exposed male Wistar rats to 3 weeks of CHH and thereafter removed the hypoxic stimulus for 3 and 6 weeks, respectively. Adaptation to 3 weeks of CHH increased the RV to left ventricle (LV) plus interventricular septum ratio by increased (223.5 ± 7.03 vs. 397.4 ± 29.8, p<0.001 versus normoxic controls), indicative of RVH. Hematocrit levels, RV systolic pressure and RV developed pressure (RVDP) were increased in parallel. Mitochondrial respiratory capacity was not significantly altered when using both carbohydrate and fatty acid oxidative substrates. After the 3-week normoxia recovery period, the RV to LV ratio was increased but to a lesser extent compared to the 3-week hypoxic time-point, i.e. 244.7 ± 11.2 vs. 349.64 ± 3.8, p<0.001 versus normoxic controls. Moreover, hematocrit levels were completely normalized. However, the RV systolic pressure and the functional adaptations, i.e. increased RVDP induced by CHH exposure still persisted in the 3-week recovery (3HRe) group. Also, pyruvate utilization was increased versus matched controls (p<0.04 vs. matched controls). Interestingly, we found that at the 6-week recovery time point functional parameters were largely normalized. However, the RV to LV ratio was still increased by 269.3 ± 14.03 vs. 333.9 ± 11.7, p<0.0001 vs. matched controls. Furthermore, palmitoylcarnitine utilization was increased (p<0.03 vs. matched controls). In conclusion, we found that exposure to CHH resulted in various adaptive physiological changes, i.e. enhanced hematocrit levels, increased RV mass linked to greater RV contractility and respiratory function. It is important to note that all these changes only occurred in the RV and not in the LV. Furthermore, when a normoxic recovery period (3 and 6 weeks, respectively) were initiated, these physiological parameters largely normalized. Together, the findings of this thesis clearly show the establishment of a reversible model of RV physiological hypertrophy. Our future work will focus on disrupting signaling pathways underlying this process and to thereafter ascertain whether reversibility is abolished. Elucidation of such targets should provide a unique opportunity to develop novel therapeutic agents to treat patients and thereby reduce the burden of heart disease.

The beneficial impact of regular physical activity on cardiovascular health is well established. However, the ideal amount of exercise required to provide these benefits is not well defined, with some recent reports showing no further cardiovascular benefits and even detrimental effects when performing exercise with high training loads, particularly for endurance sports disciplines. Indeed, during the last two decades, an increasing amount of data has related high endurance training loads with an increased susceptibility for atrial arrhythmias as well as with a detrimental right ventricle remodelling. In our study, we analysed structural and functional acute changes after an endurance race at three different distances and demonstrated a dose-response relationship between endurance exercise “doses” and acute impairment in right ventricular (RV) and atrial performance without left ventricle involvement. However, high interindividual variability was observed between participants performing the same amount of exercise. We identified different patterns of RV and atrial adaptation to exercise and highlighted RV diastolic dysfunction at rest as a potential early sign of RV maladaptation to exercise. Although we could not determine if these acute RV and atrial changes induced by a bout of endurance exercise would persist or are reversible, our experimental model of long-term endurance exercise showing impairment in RV performance promoted by very high endurance training loads suggested that, independently of individual factors, there is a threshold for safe exercise, determined by both intensity and duration, beyond which cardiac adaptation might be no longer benign but become deleterious. Additionally, we observed that the RV segments showed different adaptations to exercise, with the basal segment playing the major role in increasing stroke volume during exercise but also, due to its thinner wall and bigger cavity, being more vulnerable to the exercise-induced high wall stress, compared to the RV apex. Finally, we showed that long-term endurance training promoted a similar cardiac remodelling in both men and women. However, male athletes had larger right heart cavities and lower atrial and ventricular deformation values, compared to female athletes. These results imply that the right heart cavities of male athletes work under different conditions in maintaining RV and atrial stroke volume, with larger volumes and lower myocardial deformation. Thus, they are provided with an enhanced functional reserve during exercise but also work with increased atrial and RV wall stress. The mechanism underlying these gender-related differences in atrial and RV remodelling in response to exercise and the clinical significance of the findings warrant further investigation
Los efectos beneficiosos de la actividad física regular sobre la salud cardiovascular son incuestionables. Sin embargo, la cantidad óptima de ejercicio para proporcionar estos beneficios no está aún bien establecida, sugiriéndose que altas cargas de entrenamiento podrían llegar incluso a tener efectos deletéreos. De hecho, varias publicaciones han relacionado el entrenamiento de resistencia con una mayor susceptibilidad a arritmias auriculares y con un remodelado patológico del ventrículo derecho (VD). En el presente estudio, analizamos los cambios agudos experimentados por el corazón tras la realización de una carrera de resistencia con tres distancias distintas y demostramos una relación dosis- respuesta entre el empeoramiento en el funcionamiento del VD y las aurículas y la carga de ejercicio realizada. Sin embargo, objetivamos una gran variabilidad inter-individual entre participantes que ejecutaron la misma carga de ejercicio. Identificamos distintos patrones de adaptación del VD y las aurículas al ejercicio de resistencia y señalamos como la disfunción diastólica del VD en reposo podría ser un signo incipiente de mala adaptación al ejercicio. Aunque no pudimos determinar la persistencia o temporalidad de estos cambios, nuestro modelo experimental demostró un empeoramiento de la funcionalidad del VD inducida por el entrenamiento de resistencia, sugiriendo que, independientemente de factores individuales, hay un verdadero límite para la práctica deportiva segura, determinado por la intensidad y la duración, a partir del cual la adaptación cardíaca al ejercicio podría pasar de fisiológica a patológica. Por otra parte, observamos que los segmentos del VD muestran diferentes adaptaciones al ejercicio, siendo el basal el que juega un mayor papel en el aumento del volumen latido durante el ejercicio, pero también el más vulnerable al estrés de pared inducido por el ejercicio. Finalmente, objetivamos que el entrenamiento de resistencia indujo un remodelado cardiaco similar en ambos géneros. Sin embargo, los varones mostraron cavidades derechos mayores y menores valores de deformación miocárdica tanto a nivel ventricular como auricular que las mujeres. Estos hallazgos sugieren que las cavidades cardiacas derechas de los hombres deportistas, trabajan en condiciones diferentes para mantener el volumen latido, con volúmenes mayores y menor deformación; lo cual implica una reserva funcional aumentada durante la práctica de ejercicio pero también un mayor estrés de pared auricular y ventricular.

Introdução: A fração de ejeção do ventrículo direito (FEVD) é um importante fator prognóstico em pacientes com hipertensão pulmonar (HP), porém a sua medida é complicada e demorada devido à complexidade anatômica do ventrículo direito (VD). O TAPSE (Tricuspid Annular Plane Systolic Excursion) é um bom índice da FEVD, mas ele avalia apenas o componente longitudinal da contração ventricular direita. A RVFAC (Right Ventricular Fractional Area Change) parece ser um melhor índice da FEVD por incluir os componentes longitudinal e transversal da contração ventricular direita. O objetivo deste estudo foi avaliar a performance da RVFAC de acordo com a gravidade do acometimento hemodinâmico em dois grupos distintos de pacientes portadores de HP pré-capilar: hipertensão arterial pulmonar (HAP) e tromboembolismo pulmonar crônico hipertensivo (TEPCH). Métodos: 62 pacientes realizaram cateterismo cardíaco direito e ressonância magnética cardíaca em ±72h. As áreas sistóica e diastólica finais do ventrículo direito (ASFVD, ADFVD), a área diastólica final do ventrículo esquerdo (ADFVE) e o TAPSE foram medidos nas imagens de quatro cavidades. A RVFAC (ADFVD-ASFVD/ADFVD) e a relação entre as áreas diastólica finais ventriculares (ADFVD/ADFVE) foram calculadas. Os diâmetros entre as paredes livre e septal (dL-S) e antero-posterior (dA-P) do ventículo esquerdo (VE) foram medidos nas imagens em eixo curto e o índice de excentricidade do VE (IE) foi calculado (=dA-P/dL-S). A FEVD foi calculada a partir de imagens consecutivas de 6mm no eixo curto. . Resultados: A população tinha 58 anos em média, a maioria era do sexo feminino e estava em classe funcional III, 23 tinham HAP e 39 TEPCH. A FEVD apresentou correlações fracas com as medidas hemodinâmicas de sobrecarga e de função do VD. A RVFAC apresentou melhor correlação (R2=0,65, p < 0,001) do que o TAPSE (R2=0,35, p<0,001) com a FEVD e melhor capacidade para estimar FEVD<35% do que o TAPSE (TAPSE: AUC 0,73 e RVFAC: AUC 0,93, p=0,0065). Dividimos a população pela mediana da resistência vascular pulmonar (RVP) e observamos que no grupo com maior gravidade hemodinâmica essa diferença se acentuou: no grupo com RVP<8,5UW (RVFAC: R2=0,66, p<0,001 e TAPSE: R2=0,30, e p=0,002) e no grupo com RVP>8,5UW (RVFAC: R2=0,51, p<0,001 e TAPSE: R2=0,14, e p=0,041). O grupo com RVP>8,5UW apresentou maior ADFVD/ADFVE e maior IE. As correlações da RVFAC e TAPSE com FEVD foram semelhantes entre os grupos HAP e TEPCH. Conclusão: A RVFAC se correlacionou melhor com a FEVD do que o TAPSE tanto no grupo com menor como no grupo com maior gravidade hemodinâmica. No grupo com maior gravidade as correlações da RVFAC com a FEVD foram ainda mais significativas, não havendo diferenças na performance da RVFAC entre os pacientes com HAP e TEPCH. A RVFAC foi um melhor índice da FEVD talvez por incluir o movimento transversal da contração ventricular
Introduction: The right ventricular ejection fraction (RVEF) is a surrogate marker in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The TAPSE (Tricuspid Annular Plane Systolic Excursion) is a good index of RVEF, though it measures only the longitudinal component of right ventricular contraction. The RVFAC (Right Ventricular Fractional Area Change) seems to be a better index of RVEF because it takes into account the longitudinal and the transversal components of right ventricular contraction. The aim of our study was to evaluate the RVFAC performance according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methos: Sixty-two patients with PAH and CTEPH underwent right heart catheterization and cardiac MR in a 72-hour delay. The right and left ventricle end diastolic areas (RVEDA, LVEDA), the right ventricle end systolic area (RVESA) and TAPSE were measured in the four chamber view. The RVFAC (=RVEDARVESA/RVEDA) and the RVEDA/LVEDA relationship were calculated. The diameter between the left ventricle (LV) free wall and the septum (dF-S) and the diameter between the LV anterior and posterior walls (dA-P) were measured and the LV eccentricity index (EI) was calculated (=dA-P/dF-S). The RVEF was calculated by using 6 mm RV short axis cines. Results: The population had mean age of 58 years with female majority, most of the patients were in functional class III, 23 had PAH and 39 CTEPH. The RVEF was weakly correlated to the hemodynamic variables of RV afterload and function. The RVFAC was more strongly correlated to RVEF (R2=0.65, p<0.001) than TAPSE (R2=0.35, p<0.001). RVEF<35% was better predicted by RVFAC than TAPSE (TAPSE: AUC 0.73 and RVFAC: AUC 0.93, p=0.0065). We divided the population by the median of the pulmonary vascular resistance (PVR) and we observed that in the group with worse hemodynamic severity this difference increased: in the group with PVR<8,5WU (RVFAC: R2=0.66, p<0.001 and TAPSE: R2=0.30, p=0.002) and in the group with PVR>8,5 WU (RVFAC: R2=0.51, p<0.001 and TAPSE: R2=0.14, p=0.041). The group with PVR>8,5WU had an increased RVEDA/LVEDA and an increased EI. There was no differences in the RVEF relationships between the groups of PAH and CETPH. Conclusion: The RVFAC was better correlated to RVEF than TAPSE in the groups with less severe and more severe hemodynamics. In patients with increased hemodynamic severity RVFAC perfomed even better, there was no difference in the performance of RVFAC in PAH or CTEPH. RVFAC was a better index of RVEF possibly because it takes into account the transversal component of right ventricular function

[EN] Heart failure (HF) constitutes a major public health problem worldwide. Operationally it is defined as a clinical syndrome characterized by the marked and progressive inability of the ventricles to fill and generate adequate cardiac output to meet the demands of cellular metabolism that may have significant variability in its etiology and it is the final common pathway of various cardiac pathologies. Much attention has been paid to the understanding of the arrhythmogenic mechanisms induced by the structural, electrical, and metabolic remodeling of the failing heart. Due to the complexity of the electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes equivocal. Nevertheless, a number of common features of failing hearts have been documented. At the cellular level, prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. At the tissue level, intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. In this Thesis a computational model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of the late sodium current (INaL) in order to study the arrhythmogenic processes due to failing phenotype. Experimental data from several sources were used to validate the model. Due to extensive literature in the subject a sensitivity analysis was performed to assess the influence of main ionic currents and parameters upon most related biomarkers. In addition, multiscale simulations were carried out to characterize this pathology (transmural cardiac fibres and tissues). The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of calcium homeostasis of failing myocytes. Our strand simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration (APD) and repolarization time (RT). Conduction velocity (CV) and the safety factor for conduction (SF) were also reduced by the progressive structural remodeling during heart failure. In our transmural ventricular tissue simulations, no reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the vulnerable window (VW). However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In conclusion, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In that sense, structural remodeling is a key factor in the genesis of vulnerability to reentry, mainly at intermediates levels of fibrosis and intercellular uncoupling.
[ES] La insuficiencia cardíaca (IC) constituye un importante problema de salud pública en todo el mundo. Operacionalmente se define como un síndrome clínico caracterizado por la incapacidad marcada y progresiva de los ventrículos para llenar y generar gasto cardíaco adecuado para satisfacer las demandas del metabolismo celular, que puede tener una variabilidad significativa en su etiología y es la vía final común de varias patologías cardíacas. Se ha prestado mucha atención a la comprensión de los mecanismos arritmogénicos inducidos por la remodelación estructural, eléctrica, y metabólica del corazón afectado de IC. Debido a la complejidad de los cambios electrofisiológicos que pueden ocurrir durante la IC, la literatura científica es compleja y, a veces equívoca. Sin embargo, se han documentado una serie de características comunes en corazones afectados de IC. A nivel celular, se han establecido como las características distintivas de los miocitos aislados de corazones afectados de IC la prolongación del potencial de acción (PA), que implica la remodelación de los canales iónicos y las alteraciones en la dinámica del calcio. A nivel de los tejidos, el desacoplamiento intercelular y la fibrosis se identifican como los principales factores arritmogénicos. En esta tesis se propuso un modelo celular computacional para la insuficiencia cardíaca utilizando una versión modificada del modelo de potencial de acción ventricular humano de Grandi y colaboradores que incorpora la formulación de la corriente tardía de sodio (INaL) con el fin de estudiar los procesos arritmogénicas debido al fenotipo de la IC. Los datos experimentales de varias fuentes se utilizaron para validar el modelo. Debido a la extensa literatura en la temática se realizó un análisis de sensibilidad para evaluar la influencia de las principales corrientes iónicas y los parámetros sobre los biomarcadores relacionados. Además, se llevaron a cabo simulaciones multiescala para caracterizar esta patología (en fibras y tejidos transmurales). El modelo propuesto para la corriente tardía de sodio y la remodelación electrofisiológica de los miocitos de corazones afectados de IC reprodujeron con precisión las observaciones experimentales. Una INaL incrementada parece ser un importante contribuyente al fenotipo electrofisiológico y la desregulación de la homeostasis del calcio de los miocitos afectados de IC. Nuestros resultados de la simulaciones en fibra ilustran cómo la presencia de células M y el remodelado electrofisiológico heterogéneo en el ventrículo humano afectado de IC modulan la dispersión de la duración potencial de acción (DPA) y el tiempo de repolarización (TR). La velocidad de conducción (VC) y el factor de seguridad para la conducción (FS) también se redujeron en la remodelación estructural progresiva durante la insuficiencia cardíaca. En nuestras simulaciones transmurales de tejido ventricular, no se observó reentrada en condiciones normales o en presencia de la remodelación iónica de la IC. Sin embargo, determinadas cantidades de fibrosis y / o desacoplamiento celular eran suficientes para provocar la actividad reentrante. En condiciones donde se había generado la reentrada, el remodelado electrofisiológico de la IC no alteró la anchura de la ventana vulnerable (VV). Sin embargo, niveles intermedios de fibrosis y el desacoplamiento celular ampliaron significativamente la VV. En conclusión, niveles elevados de fibrosis en corazones afectados de IC, así como la reducción de acoplamiento intercelular, se combinan para aumentar los gradientes electrofisiológicos y reducir la propagación eléctrica. En ese sentido, la remodelación estructural es un factor clave en la génesis de la vulnerabilidad a las reentradas, principalmente en niveles intermedios de fibrosis y desacoplamiento intercelular. El remodelado electrofisiológico promueve la arritmogénesis y puede ser alterado dependi
[CAT] La insuficiència cardíaca (IC) constitueix un important problema de salut pública arreu del món. A efectes pràctics, es defineix com una síndrome clínica caracteritzada per la incapacitat marcada i progressiva dels ventricles per omplir i generar el cabal cardíac adequat, per tal de satisfer les demandes del metabolisme cel·lular, el qual pot tenir una variabilitat significativa en la seua etiologia i és la via final comuna de diverses patologies cardíaques. S'ha prestat molta atenció a la comprensió dels mecanismes aritmogènics induïts per la remodelació estructural, elèctrica, i metabòlica del cor afectat d'IC. A causa de la complexitat dels canvis electrofisiològics que poden ocórrer durant la IC, trobem que la literatura científica és complexa i, de vegades, equívoca. No obstant això, s'han documentat una sèrie de característiques comunes en cors afectats d'IC. A nivell cel·lular, com característiques distintives dels miòcits aïllats de cors afectats d'IC, s'han establert la prolongació del potencial d'acció (PA), que implica la remodelació dels canals iònics, i les alteracions en la dinàmica del calci. A nivell dels teixits, el desacoblament intercel·lular i la fibrosi s'identifiquen com els principals factors aritmogènics. Per tal d'estudiar els processos aritmogènics a causa del fenotip de la IC, es va proposar un model cel·lular computacional d'IC utilitzant una versió modificada del model de potencial d'acció ventricular humà de Grandi i els seus col·laboradors, el qual incorpora la formulació del corrent de sodi tardà (INaL). Amb l'objectiu de validar el model es van utilitzar dades experimentals de diverses fonts. A causa de l'extensa literatura en la temàtica, es va realitzar una anàlisi de sensibilitat per tal d'avaluar la influència de les principals corrents iòniques i els paràmetres sobre els biomarcadors relacionats. A més, es van dur a terme simulacions multiescala per a la caracterització d'aquesta patología (fibres i teixits transmurals). El model proposat per al corrent de sodi tardà i la remodelació electrofisiològica dels miòcits de cors afectats d'IC van reproduir amb precisió les observacions experimentals. Una INaL incrementada sembla contribuir de manera important al fenotip electrofisiològic i a la desregulació de l'homeòstasi del calci dels miòcits afectats d'IC. Els resultats de les nostres simulacions en fibra indiquen que la presència de cèl·lules M i el remodelat electrofisiològic heterogeni en el ventricle humà afectat d'IC modulen la dispersió de la durada del potencial d'acció (DPA) i el temps de repolarització (TR). La velocitat de conducció (VC) i el factor de seguretat per a la conducció (FS) també es van reduir en la remodelació estructural progressiva durant la IC. A les nostres simulacions transmurals de teixit ventricular, no s'observà cap reentrada ni en condicions normals ni en presència de la remodelació iònica de la IC. No obstant això, amb determinades quantitats de fibrosi i/o desacoblament cel·lular sí que es provocà l'activitat reentrant. I amb les condicions que produïren la reentrada, el remodelat electrofisiològic de la IC no va alterar l'amplada de la finestra vulnerable (FV). Tanmateix, nivells intermedis de fibrosi i el desacoblament cel·lular sí que ampliaren significativament la FV. En conclusió, nivells elevats de fibrosi en cors afectats d'IC, així com la reducció d'acoblament intercel·lular, es combinen per augmentar els gradients electrofisiològics i reduir la propagació elèctrica. Per tant, la remodelació estructural és un factor clau en la gènesi de la vulnerabilitat a les reentrades, principalment en nivells intermedis de fibrosi i desacoblament intercel·lular.
Gómez García, JF. (2015). Multiscale Modeling and Simulation of Human Heart Failure [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/52389
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