Dissertations / Theses on the topic 'Cardiac electromechanics'

Cardiac arrhythmia is a leading cause of death in the developed world and a final common pathway for many forms of cardiac disease. Rare inherited arrhythmia syndromes contribute to this disease burden, particularly through sudden death in the young. The study of rare syndromes, such as inherited arrhythmia, can also identify genes and pathways important in common diseases. Here, genomic approaches were applied to dissect genetic determinants of cardiac arrhythmia, through gene discovery, variant discovery, and variant annotation. First, whole-exome sequencing was used to identify the genetic basis of an unexplained inherited arrhythmia syndrome. Linkage analysis and conventional sequencing excluded known causative genes in a family with Brugada Syndrome, and whole exome sequencing identifie d a shortlist of five new candidate genes that may lead to a genetic diagnosis in this family and new insights into the pathogenesis of the condition. Following the identification of genes responsible for inherited arrhythmia syndromes, the recognition of specific disease-causing variants in those genes allows for clinical application, including molecular diagnosis, cascade screening and stratified therapy. Here, two high-throughput next-generation sequencing approaches for the detection of variants in these genes were compared, technically evaluated, and optimis ed. This represents the de novo establishment of next-generation sequencing technologies and analysis pathways in our laboratory, and provides a platform for molecular diagnosis and future genotype-phenotype correlation studies. Finally, a novel approach for the functional annotation of non-synonymous variants was developed. This approach, termed 'Paralogous Annotation', identifies functionally important, disease-associated residues across protein families using multiple sequence alignment. Paralogous Annotation was validated here by demonstrating the accurate identification of disease-causing variation in genes that cause long QT syndrome - an important cause of sudden death. This methodology is widely applicable to annotate Mendelian human disease genes.

Thesis (M.S.)--University of California, San Diego, 2009.
Title from first page of PDF file (viewed October 20, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 86-91).

This thesis describes the development of a framework for computational modelling of electromechanics in the mouse, with the purpose of being able to integrate cellular and tissue scale observations in the mouse and investigate physiological hypotheses. Specifically, the framework is applied to interpret electromechanical coupling mechanisms and the progression of heart failure in genetically modified mice. Chapter 1 introduces the field of computational biology and provides context for the topics to be investigated. Chapter 2 reviews the biological background and mathematical bases for electromechanical models, as well as their limitations. In Chapter 3, a set of efficient computational methods for coupled cardiac electromechanics was developed. Among these are a modified Newton method combined with a solution predictor which achieves a 98% reduction in computational time for mechanics problems. In Chapter 4, this computational framework is extended to a multiscale electromechanical model of the mouse. This electromechanical model includes our novel cardiac cellular contraction model for mice, which is able to reproduce murine contraction dynamics at body temperature and high pacing frequencies, and provides a novel explanation for the biphasic force-calcium relation seen in cardiac myocytes. Furthermore, our electromechanical model of the left ventricle of the mouse makes novel predictions on the importance of strong velocity-dependent coupling mechanisms in generating a plateau phase of ventricular pressure transients during ejection. In Chapter 5, the framework was applied to investigate the progression of heart failure in genetically modified 'Serca2 knockout' mice, which have a major disruption in mechanisms governing calcium regulation in cardiac myocytes. Our modelling framework was instrumental in showing for the first time the incompatibility between previously measured cellular calcium transients and ventricular ejection. We were then able to integrate new experimental data collected in response to these observations to show the importance of beta-adrenergic stimulation in the progression of heart failure in these knockout mice. Chapter 6 presents the conclusions and discusses possibilities for future work.

Cardiac motion is a highly complex and integrated process of vital importance as it sustains the primary function of the heart, that is pumping blood. Cardiac tissue microstructure, in particular the alignment of myocytes (also referred to as fibre direction) and their lateral organisation into laminae (or sheets), has been shown by both experimental and computational research to play an important role in the determination of cardiac motion patterns. However, current models of cardiac electromechanics, although already embedding structural information in the models equations, are not yet able to fully reproduce the connection between structural dynamics and cardiac deformation. The aim of this thesis was to develop an electromechanical modelling framework to investigate the impact of tissue structure on cardiac motion, focussing on left ventricular contraction in rat. The computational studies carried out were complemented with a preliminary validation study based on experimental data of tissue structure rearrangement during contraction from diffusion tensor MRI.

The focus of this thesis is the development and application of personalised computational models of cardiac electromechanics to understand and ultimately inform cardiac resynchronisation therapy (CRT). To achieve this goal, a semi-automatic pipeline for the generation and parameterisation of detailed biophysically based models using clinical data is presented and applied to a cohort of patients. Specifically, an anatomically based finite element model has been developed and applied to simulate cardiac electromechanics through the coupling of the monodomain and large deformation mechanics governing frameworks. Techniques have been implemented for tting high order representations of cardiac anatomy from MRI data, and myocardial conductivity, sti ness, contractility and boundary conditions from endocardial activation recordings and pressure volume loops respectively. Embedding these tting steps within a semi-automatic pipeline, this personalisation work ow has been applied to four CRT patient data sets. Three models were successfully fitted, while the response of a fourth patient to therapy could not be captured with our framework. It is important to note that for this fourth case the recorded response to therapy in this individual was considered, by standard clinical measures, to be an outlier. Seven metrics of cardiac electrophysiology, haemodynamics and energetics were computed from the models of each patient and used to quantify the effects of changes resulting from CRT. Differences between patient cases were analysed, revealing that reductions in total activation time with pacing (correlation between changes across individuals in our virtual patient cohort p= - 0:73) and transmural conduction block were associated with greater acute haemodynamic response (AHR) (97:1% of models in a virtual patient cohort had a greater AHR with block). Patients with a strong AHR also beneffited from increased stroke work ( p = 0:50) and reduced left ventricle (LV) myocardial work ( p = -0:77) , implying an improvement in myocardial efficiency, plus a homogenisation of LV myocardial work ( p = -0:62). Maps of AHR by LV epicardial pacing site during simultaneous biventricular pacing were generated, and the optimal region for pacing was determined. Optimisation of pacing lead location to maximise AHR was seen to benefifrom improved stroke work and reduced total LV myocardial work and LV work heterogeneity across all patients.

In this thesis a coupled model of cardiac electromechanical activity is presented, using the finite element method to model both electrophysiology and mechanics within a deforming domain. The efficiency of the electrical model was improved using adaptive mesh refinement and the mechanical system performance was improved with the addition of preconditioning. Unstructured triangular meshes were used throughout. The electrophysiology model uses the ten Tusscher-Panfilov 2006 detailed cellular model, and includes anisotropic diffusion, uses a semi-implicit time stepping scheme, stores data in an efficient sparse storage format and applies a Reverse Cuthill-McKee ordering algorithm to reduce the matrices’ bandwidths. Linear elements were used to approximate the transmembrane voltage and spatial and temporal convergence tests were undertaken. Local mesh adaptivity is added to the electrical component of the model and improvements to the performance and efficiency gained by this technique were investigated. Two different monitor functions were utilised and these demonstrated that by targeting adaptive mesh refinement at the front of the electrical wave significant efficiency and performance benefits could be achieved. The cardiac mechanical model is based on finite deformation elasticity theory, enforces the incompressibility of the tissue and incorporates anisotropic tension to simulate fibre orientation. This uses isoparametric quadratic elements for deformation, linear elements for pressure, was integrated with numerical quadrature and the resulting non-linear system solved with the iterative Newton method. Preconditioning was added to the mechanical component of the model and improvements in the performance of the solver due to this were investigated. An ILUT (Incomplete Lower Upper factorisation with drop Tolerance) preconditioner was implemented and this demonstrated performance improvements of up to 27 times on the meshes tested. The resulting cardiac electromechanical solver was then used to consider how known changes in cardiac electrophysiology, which are manifest in end-stage heart disease, affect the stability of the electrical wave. Specifically, investigations were undertaken into the introduction of fibrotic regions (with different sizes and concentrations) and electrical remodelling caused by end-stage cardiac disease. These were modelled on both static and deforming domains to consider whether deformation can alter the stability of a spiral wave. These simulations demonstrated that fibrotic regions and tissue deformation can have significant disruptive effects on the stability of a re-entrant spiral wave and that remodelling the electrophysiology stabilises the wave.

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Doenças cardiovasculares estão relacionadas com um alto índice de mortalidade no mundo. Tendo isto em vista, a modelagem computacional cardíaca tornou-se uma ferramenta importante no suporte ao teste de novas drogas e no desenvolvimento de novos equipamentos e técnicas de diagnóstico. O objetivo deste trabalho é o estudo e desenvolvimento de novos modelos para o acoplamento eletromecânico de células e tecidos cardíacos, em especial do ventrículo esquerdo, que é a principal estrutura responsável pelo bombeamento do sangue para o corpo. Este trabalho foi dividido em duas principais etapas: 1) Desenvolvimento de um novo modelo para a eletromecânica dos cardiomiócitos do ventrículo esquerdo humano, a partir do acoplamento de dois modelos preexistentes, um para a eletrofisiologia e outro para a geração de força ativa nos miofilamentos. No desenvolvimento do modelo, técnicas de otimização como algoritmos genéticos foram utilizadas para o ajuste de parâmetros de forma que o modelo reproduzisse os escassos dados experimentais para humanos encontrados na literatura. 2) A incorporação deste modelo em simulações de maior escala, em nível de tecido. Tratamos neste trabalho os problemas numéricos e metodológicos que esta incorporação acarreta. Além disso, analisamos a influência da deformação mecânica em características eletrofisiológicas, como a forma da onda de eletrogramas ventriculares.
Cardiac diseases are associated with high mortality rates around the globe. With this in mind, cardiac computational modeling has become an important tool to support the test of new drugs, the development of new devices and of diagnostic techniques. The objective of this work is the study and development of new models for the electromechanical coupling of heart cells and tissues, in particular the left ventricle, which is the main structure responsible for pumping blood to the body. This work can be divided in two main steps: 1) The development of a new model for the electromechanics of human left ventricle cardiac myocytes, based on the coupling of two existing models, one for the electrophysiology and another for the myofilament active force generation. On the development of this model optimization techniques like genetic algorithms where used for the parameter adjustment to reproduce the few experimental data available in the literature. 2) This model was embedded in larger scale electromechanical simulations, i.e. tissue level. This work treats the numerical and methodological problems that this coupling brings. Furthermore, we analyze the influence of the mechanical deformation in important eletrophysiological features, such as the waveform of ventricular electrograms.

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A simulação da atividade eletromecânica do coração é uma ferramenta relevante para a interpretação e estudos de medidas fisiológicas e diversos fenômenos cardíacos. Entretanto, modelos computacionais para este propósito podem ser computacionalmente custosos. Assim, são propostos neste trabalho três modelos simplificados, a nível celular, que foram capazes de reproduzir de forma quantitativa o fenômeno da contração de miócitos cardíacos. Para obtenção destes modelos um ajuste de parâmetros foi realizado via algoritmos genéticos. Os modelos propostos com parâmetros ajustados apresentaram resultados satisfatórios para reprodução da força ativa do coração com a vantagem de serem baseados em apenas duas equações diferenciais ordinárias. Além disso, o modelo final foi validado utilizando simulações envolvendo extra-sístoles, sendo capaz de reproduzir o fenômeno de alternância na força ativa.
The simulation of the heart electromechanical activity is a relevant tool for the interpretation and studies of physiological measures and various cardiac phenomena. However, computational models for this purpose may be computationally costly. Thus, three simplified models which were able to quantitatively reproduce the phenomenon of cardiac myocyte contraction were proposed in this work. At the cellular level, they were able to quantitatively reproduce the phenomenon of cardiac myocyte contraction. A parameter adjustment via genetic algorithm was performed to obtain these models. The proposed models with adjusted parameters presented satisfactory results for the reproduction of the active force of the heart with the advantage of being based on only two ordinary differential equations. In addition, the final model was validated using simulations involving extra-systoles, being able to reproduce the phenomenon of alternation in the active stress.

Cardiovascular diseases are nowadays one of the major causes of death in developed countries. Besides the already known risk factors such as lifestyle and genetics, there is a growing evidence that adverse remodelling during prenatal life presents a risk factor for some cardiovascular diseases at later life. Recent studies have demonstrated that fetuses with intra-uterine growth restriction show cardiovascular remodelling at organ, vascular and also cellular and subcellular level, and moreover these changes persist postnatally. However this is a complex mechanism that needs to be further investigated. Currently, Doppler ultrasonography is one of the techniques most used to assess the fetal cardiovascular status and to study the heart and vascular remodelling in clinical practice. However, some of underlying hemodynamic and vascular changes cannot be assessed clinically and more sophisticated techniques are needed. Computational modelling of biological systems arises as a powerful tool to overcome this challenge, to support clinicians and to improve the understanding of different pathologies. In this thesis we proposed the use of computational models of fetal circulation, of cardiac cells and also image-processing tools, to improve the understanding of intra-uterine cardiac remodelling that takes place at different scales of the fetal cardiovascular system, and also to estimate the patient-specific hemodynamic properties that cannot be directly assessed from clinical measurements. The results arising from this thesis demonstrate that computational models are able to improve the understanding and detection of the intra-uterine cardiovascular remodelling by means of patient-specific simulations.
Les malalties cardiovasculars són avui en dia una de les principals causes de mortalitat en països desenvolupats. Deixant de banda els factors de risc relacionats amb l'estil de vida i la genètica, existeix una creixent evidència de què la remodelació adversa durant la vida prenatal esdevé un factor de risc per a algunes malalties cardiovasculars en l'edat adulta. S'ha demostrat que els fetus amb restricció de creixement intrauterina mostren signes de remodelació cardiovascular tant a nivell d'òrgan, vascular com a nivell cel•lular i subcel•lular, i molts cops aquests canvis persisteixen postnatalment. No obstant, és tracta d'un mecanisme complex que necessita ser investigat en profunditat. Actualment, l'ecografia Doppler és una de les tècniques més empradres per avaluar l'estat cardiovascular fetal i per estudiar la remodelació tant cardiaca com vascular durant la pràctica clínica. No obstant, alguns dels canvis hemodinàmics i vasculars subjacents no es poden avaluar clínicament, requerint de tècniques més sofisticades. El modelatge computacional de sistemes biològics es presenta com un potent instrument per superar aquest repte, per donar suport als metges i millorar la comprensió de les diferents patologies. En aquesta tesi es presenta per una banda l'ús de models computacionals tant de la circulació fetal com també de la cèl•lula cardíaca i la utilització d'eines de processat d'imatge amb la finalitat de millorar la comprensió de la remodelació cardiovascular intrauterina que té lloc a diferents escales del sistema cardiovascular fetal, i estimar les propietats hemodinàmiques específiques de cada pacient, les quals no es poden extreure directament a partir de mesures clíniques. Els resultats derivats d'aquesta tesi demostren que els models computacionals són capaços de millorar la comprensió i la detecció de la remodelació cardiovascular intrauterina mitjançant simulacions específiques del pacient.

La modélisation du vivant, en particulier la modélisation de l'activité cardiaque, est devenue un défi scientifique majeur. Le but de cette thématique est de mieux comprendre les phénomènes physiologiques et donc d'apporter des solutions à des problèmes cliniques. Nous nous intéressons dans cette thèse à la modélisation et à l'étude numérique de l'activité électrique du cœur, en particulier l'étude des électrocardiogrammes (ECGs). L'onde électrique dans le cœur est gouvernée par un système d'équations de réaction-diffusion appelé modèle bidomaine ce système est couplé à une EDO représentant l'activité cellulaire. Afin simuler des ECGs, nous tenons en compte la propagation de l'onde électrique dans le thorax qui est décrite par une équation de diffusion. Nous commençons par une démonstrer l'existence d'une solution faible du système couplé cœur-thorax pour une classe de modèles ioniques phénoménologiques. Nous prouvons ensuite l'unicité de cette solution sous certaines conditions. Le plus grand apport de cette thèse est l'étude et la simulation numérique du couplage électrique cœur-thorax. Les résultats de simulations sont représentés à l'aide des ECGs. Dans une première partie, nous produisons des simulations pour un cas normal et pour des cas pathologiques (blocs de branche gauche et droit et des arhythmies). Nous étudions également l'impact de certaines hypothèses de modélisation sur les ECGs (couplage faible, utilisation du modèle monodomaine, isotropie, homogénéité cellulaire, comportement résistance-condensateur du péricarde,. . . ). Nous étudions à la fin de cette partie la sensibilité des ECGs par apport aux paramètres du modèle. En deuxième partie, nous effectuons l'analyse numérique de schémas du premier ordre en temps découplant les calculs du potentiel d'action et du potentiel extérieur. Puis, nous combinons ces schémas en temps avec un traîtement explicite du type Robin-Robin des conditions de couplage entre le cœur et le thorax. Nous proposons une analyse de stabilité de ces schémas et nous illustrons les résultats avec des simulations numériques d'ECGs. La dernière partie est consacrée à trois applications. Nous commençons par l'estimation de certains paramètres du modèle (conductivité du thorax et paramètres ioniques). Dans la deuxième application, qui est d'originie industrielle, nous utilisons des méthodes d'apprentissage statistique pour reconstruire des ECGs à partir de mesures ('électrogrammes). Enfin, nous présentons des simulations électro-mécaniques du coeur sur une géométrie réelle dans diverses situations physiologiques et pathologiques. Les indicateurs cliniques, électriques et mécaniques, calculés à partir de ces simulations sont très similaires à ceux observés en réalité.

碩士
國防醫學院
生理學研究所
83
In human atrial fiber, DN-33 (10μM) decreased the rate of upstroke (Vmax) and the duration of action potential at 90% repolarization (APD90), and inhibited the automatic rhyme. In canine Purkinje fibers, DN-33 decreased the twitch tension in a concentration-dependent manner, reduced Vmax and aiNa, and shortened APD90. The amplitude of action potential (APA) and diastolic membrane potential (MDP) were not changed. In guinea pig ventricular papillary muscles, DN-33 also attenuated the twitch tension in a concentration-dependent manner, decreased Vmax and aiNa, but increased APD90 and had no effects on MDP, APA, and pHi. Except a decreased contractile force, DN-33 (0.01μM) could completely abolish the electromechanical effects of phenylephrine. In the presence of DN-33, the curve of the contractile force and the maximal contractile force induced by phenylephrine were suppressed. The curve also shifted to higher concentrations. DN-33 could inhibit the automatic rhythm and the triggered arrhythmia induced by isoproterenol or ouabain in guinea pig papillary muscles. Under hypoxic state, DN-33 (10μM) slowed down the increasing rate of resting tension. The results suggest that DN-33 exerts a α1- antagonistic effect and inhibits the Na+ inward current. The fall in aiNa would in turn decreased cellular Ca+2 through the Na+-Ca+2 exchange mechanism.

After myocardial infarction, the stressed environment may cause negative cardiac remodeling. An emerging treatment option, engineered cardiac patches can be mechanically conditioned to increase alignment or electrically stimulated to enable anisotropic conduction. While proper integration with native tissue may require both stimuli, very few studies have applied both simultaneously, and only to extracted tissues. To demonstrate feasibility, a rigid electrode prototype was constructed to incorporate electrical stimulation into a commercially available mechanical conditioning system. Electrodes were assembled to fit the system’s geometry, and parameters were optimized to mimic the human heart rate. Previously, a study used 5-Azacytidine (5-Aza) to differentiate mesenchymal stem cells (MSCs) toward cardiac lineage, which was used here for proof-of-concept testing. Unexpectedly, MSCs treated with 5-Aza and electrically stimulated showed a decrease in cardiac marker troponin and an increase in MSC surface marker gene expression. In this setup, current from rigid electrodes passes through the media; however, under physiologically relevant conditions, electrical signals should propagate directly through cardiomyocytes. Therefore, a method to apply electromechanical stimulation to individual cells was explored in a point source stimulation platform. Electroconductive adhesive (ECA), a composite of silver and polydimethylsiloxane, was used to fabricate flexible elastic microelectrode arrays that provided positive and negative voltage sources to individual cells. Devices were not cytotoxic before applying an electric field; however, applied current caused electrolysis of media and cytotoxicity, even using current stimulation parameters lower than those in published studies. These findings suggest ECA electrochemical properties need more characterization and alternative materials for microelectrodes.

碩士
國立臺灣大學
藥理學研究所
83
HTW-3, -4 and -5,are synthetic tetrahydro furoquinolines found to have positive inotropic and negative chronotropic effect on rat cardiact issues. Current clamp revealed that HTW-3, -4 and-5 prolonged of the action potential duration with a concomitant decrease in action potential upstroke (dV/dt)max. The relative potency to prolong the action potential duration was HTW-3> HTW-4>>HTW-5. Voltage clamp study revealed that the relative sensitivity of ionic current to block by HTW-3, -5 was Ito>INa> ICa≒IK1, but Ito ≒ >INa≒Ca≒K1 by HTW-4. The reduction of Ito by HTWs was associated with a marked acceleration of its inactivation. The fractional inhibition of Ito by HTWs increased with the time of epolarization,suggesting that HTWs may inter act with open Ito channels. However, the inhibition of Ito was also associated with a negative shift of its steady-state inactvation curve and slowing of the rate of recovery of Ito from inactivation. The results suggest that HTWs may also interact with inactivated Ito channels. At lower concentration, HTW-3, -5 had the activities of class I and calss III-like anti- arrhythmic agents. The class I activity was characterized by the reduction of INa and a negative shift of the steady-state inactivation curve. IK1 was almost unaffected under the same concentration range. Atenolol (3 μM) only partially inhibited the inotropic effect of high dose HTW-3,-4 (100 μM). In conclusion, HTWs prolonged APD and caused positive inotropic action mainly by inhibition of Ito. The positive inotropic action of high concentration HTW-3, -4, but not HTW-5, was partially mediated by activation of β-adrenoceptors. The results suggested that ortho Cl substitution on N-methylbenzyl group (HTW-5)may lead to the loss of β effect. Whether ortho substitution of proton by other functional groups can have the same effect remains to be investigated in the future.

Cardiac diseases and conduction disorders are associated with stroke, heart failure and sudden cardiac death and are a major health concern worldwide. In the US alone, more than 14 million people suffer from heart rhythm disorders. Current mapping and characterization techniques in the clinic involve invasive procedures, which are time-consuming, costly, and may involve ionizing radiation. In this dissertation, we introduce Electromechanical Wave Imaging (EWI) as a non-invasive, ultrasound-based treatment planning tool for pre-procedure characterization and assessment of arrhythmia in the clinic. In particular, standard EWI processing methods for mapping the electromechanical wave (EW), i.e. the onset of the mechanical activity following the depolarization of the heart, are described and detailed. Next, validation of EWI is performed with 3D electromechanical mapping and the EW propagation is shown to follow the electrical activation in all four chambers of the heart. Demonstration of the value of EWI for the characterization of cardiac arrhythmia is accomplished in vivo in a large animal model. First, EWI is shown capable of localizing the earliest region of activation in the ventricles during pacing from a standard pacemaker lead, as well as during pacing from a novel biological pacemaker. Repeatability is also demonstrated between consecutive cardiac cycle during normal sinus rhythm and during pacing. Then, in the atria, we demonstrate that EWI is capable of accurately identifying focal sources while pacing from several locations in both the left and right atria. In addition to being capable of localizing the focal source, EWI is also shown capable of differentiating between endocardial and epicardial focal sources. Finally, it is shown that EWI can correctly identify regions of infarction and monitor formation of infarcts over several days, after ligation of the left anterior descending coronary artery of canine hearts. Novel processing techniques aimed at extracting quantitative parameters from EWI estimates are then developed and implemented. Details of the implementation of processing methods for estimating the velocity of the EW propagation are presented, and a study of the EW velocity values in a canine heart before and after infarct formation is conducted. Electromechanical cycle length mapping (ECLM), which is aimed at extracting local rates of electromechanical activation in the heart, is then introduced and its implementation detailed. ECLM is subsequently validated in a paced canine heart in vivo. Finally, initial clinical feasibility is demonstrated. First, in the study of treatment of chaotic arrhythmia such as in the case of atrial fibrillation patients undergoing direct current cardioversion, ECLM is shown to be able to confirm acute treatment success. Then, the clinical value of EWI in the electrophysiology lab as a treatment planning tool for the characterization of focal arrhythmia is shown in ventricular tachycardia and Wolff-Parkinson-White patients. EWI is currently only a step away from real-world clinical application. As a non-invasive, ultrasound-based imaging modality, EWI is capable of providing relevant insights into the origins of an arrhythmia and has the potential to position itself in the clinic as a uniquely valuable pre-procedure planning tool for the non-invasive characterization of focal arrhythmias.

碩士
國立臺灣大學
藥理學研究所
82
JKL 1067 和 N-Allylsecoboldine(STL-1)是兩個合成生物鹼，發現具有 增強收縮力及減慢心跳頻率之作用。 論文主要研究它們在心臟組織之電 生理及增強心收縮力之效果，並且評估它們的抗心律不整的活性。在大白 鼠心房及心室肌組織，1 到 30 uM JKL 1067 會使收縮力隨濃度增加而增 強，然而，其心房自發性跳動頻率則被減慢。 在大白鼠、天竺鼠的實驗 中，會使因冠狀動脈結紮再灌流及ouabain所誘發之心律不整恢復為正常 心律。 之效果，不會因前處理腎腺素阻斷劑而發生改變，但是會被前處 理的鉀管道阻斷劑所減弱 。 在大白鼠心室細胞中， 動作電位期間會隨 JKL 1067 濃度的增加而延長，且減慢伴隨動作電位去極化速率。JKL 1067可減少鈉電流，並且使鈉電流穩定狀態不活化曲線向負電位方向漂移 。 其恢復之時間常數也受影響而延長。 對於瞬時外流鉀電流，可使其尖 峰電流值減少，且明顯加速此電流的不活化速率。 另外，其穩定狀態不 活化曲線也受影響而向負電位方向漂移。 此藥物對鉀電流之抑制程度隨 鉗定時間延長而增加，結果表示 JKL1067 之抑制作用，可能是在此管道 打開狀態下進行。在較高的濃度下(10uM)對L型鈣電流沒有影響，上述三 種電流抑制敏感程度Ito>INa>>ICa。在低濃度下(小於 10 uM)可增加內向 整流鉀電流。 由以上結果顯示，JKL 1067 可能藉著對 Ito 的抑制作用 ，進而延長動作電位期間而產生增強收縮力之效果，其抗心律不整的活性 是由於對INa及 Ito的抑制，加上部分活化 IK1 的作用而產生。 STL-1可 產生增強心收縮力的作用，且可減慢自發性跳動頻率。增強收縮力的效果 不被前處理? 及?接受體阻斷劑所影響，但卻被前處理的鉀管道抑制劑 所抑制。在大白鼠的心室細胞，STL-1會使其動作電位期間延長。對離子 電流抑制大小程度為 INa>Ito>ICa>> IK1。對於鈉電流的抑制 ，伴隨著 使其穩定不活化狀態曲線向負電位方向移動。 抑制瞬時外流鉀電流是隨 濃度的增加而增加，且會加速瞬時外流鉀電流不活化速率， 使其穩定不 活化狀態曲線向負電位方向移動 ，但是對於其從不活化狀態恢復的速度 則不影響 。在較高濃度下，10 uM STL-1 只輕微地使鈣電流的不活化狀 態曲線向負電位方向移動。而濃度達 10uM以上時才會對內向整流鉀電流 有少部分的抑制作用 。在天竺鼠心房細胞中, 也會使其動作電位期間延 長，此延 內向整流鉀電流，及遲開性外流鉀電流的抑制有關。STL-1對 ouabain誘發之心律不整也有對抗之效果 The effects and antiarrhythmic activities of JKL 1067 and N- allylsecoboldine (STL-1), two synthetic alkaloids with positive inotropic and negative chronotropic activities, were assessed in cardiac tissues. JKL 1067 (1-30 uM) decreased heart rate and increased twitch tension in rat atria and ventricular strips. The inotropic effect was uneffected by adrenoceptor antagonist, but was reduced by K+ channel blocker. In guinea pig and rat hearts, ischemic reperfusion and ouabain induced arrhythmia was reverted to sinus rhythm. In rat ventricular cells, JKL 1067 prolonged action potential with a decrease in (dV/dt)max and INa and shifted inactivation curves in the negative direction. The recovery time constant was also prolonged. JKL 1067 reduced Ito with increased rate of inactivation and a negative shift of inactivation curve. The fractional inhibition increased with time, suggesting that JKL 1067 interacts with open Ito channels. At 10 mM, JKL 1067 did not affect ICa but caused a slight negative shift of inactivation curve. The sensitivity to JKL 1067 block was: Ito> INa>> ICa. In contrast, lower concentration of JKL 1067 (<10 uM) increased IK1. These results suggest that JKL 1067 increases contraction by inhibition of Ito and exerts antiarrhythmic activity by inhibition of Ito and INa with a partial increase of IK1. STL-1 (3-30uM) decreased heart rate, prolonged action potential and caused positive inotropic effect in rat atrial and ventricular muscles. The inotropic effect was abolished by K+ channel blocker. In rat ventricular cells, the sensitivity to block was INa> Ito> ICa>> IK1. STL-1 decreased INa with a nega- tive shift in its inactivation curve. STL-1 reduced Ito with an acceleration and a negative shift in inactivation curve. The rate of recovery from inactivation state, however, was unaffected.

碩士
國立成功大學
生物醫學工程學系
100
Because of the limited regeneration potential of cardiomyocytes, cell-based therapy has emerged as a promising treatment for cardiac repair. Heart is an extremely sophisticated organ with anisotropic structure, contractility and electro-conductivity. Here, we utilized a biocompatible, non-degradable and well-aligned electrospun patch that implantation infarcted myocardium and retard aggravation of post-infarction cardiomyopathy via mechanical supporting. Furthermore, we demonstrated that the aligned patch co-seeded with endothelial cells and neonatal cardiomyocytes significantly improved synchronized contractility and thus long-term cardiac performance. Surprisingly, we found the cardiac function would be even worse after mending of random-aligned patch co-seeded with cells. In summary, the present study provides a novel approach for cardiac repair; importantly, it also raises a valuable awareness that the anisotropic characteristic of the heart should be considered when applying cell transplantation for cardiac repair.

Atualmente, a rigidez arterial assume especial importância pelo facto de ser um marcador de doenças cardiovasculares, que são a principal causa de incapacidade e morte no mundo. O desenvolvimento de ferramentas de diagnóstico que são capazes de realizar uma quantificação exata e prematura de estados patológicos como a rigidez arterial apresenta-se como uma estratégia global para reduzir a morbidade e mortalidade cardiovascular. Com o intuito de monitorizar a onda de distensão arterial na carótida, uma tecnologia não – invasiva foi desenvolvida e testada com sucesso durante os últimos anos. Esteve dispositivo piezoelétrico permite a extração de informações clinicamente importantes sobre a rigidez arterial, apresentando-se como uma solução prática na avaliação do risco cardiovascular prematuro. Este projeto consistiu não só no início dos primeiros testes clínicos do dispositivo previamente desenvolvido com a realização de testes de repetibilidade, mas também na aplicação de ferramentas inovadoras de mineração de dados através de abordagens classificativas e de agrupamento. Por último, um caso de estudo foi realizado em doentes com estenose severa de forma a provar a utilidade desta tecnologia. Foram obtidos excelentes resultados em termos da repetibilidade entre ensaios consecutivos. Além disso, a capacidade de detetar variações fisiológicas após procedimentos cirúrgicos demonstrou a aplicabilidade clínica deste equipamento. As metodologias de mineração de dados também mostraram a sua eficácia na determinação prematura de risco cardiovascular. Palavras – Chave: Rigidez Arterial, Onda de Distensão Arterial, Sensor Piezoelétrico, Ensaios Clínicos, Mineração de Dados

Cardiac conduction abnormalities can often lead to heart failure, stroke and sudden cardiac death. Heart disease stands as the leading cause of mortality and morbidity in the United States, accounting for 30% of all deaths. Early detection of malfunctions such as arrhythmias and systolic heart failure, the two heart conditions studied in this dissertation, would definitely help reduce the burden cardiovascular diseases have on public health and overcome the current clinical challenges. The imaging techniques currently available to doctors for cardiac activation sequence mapping are invasive, ionizing, time-consuming and costly. Thus, there is an undeniable urgent need for a non-invasive and reliable imaging tool, which could play a crucial role in the early diagnosis of conduction diseases and allow physicians to choose the best course of action. The 12-lead electrocardiogram (ECG) is the current non-invasive clinical tool routinely used to diagnose and localize cardiac arrhythmias prior to intracardiac catheter ablation. However, it has limited accuracy and can be subject to operator bias. Besides, QRS complex narrowing on the clinical ECG after pacing device implantation is also used for response assessment in patients undergoing Cardiac Resynchronization Therapy (CRT). The latter is an established treatment for systolic heart failure patients who have Left Bundle Branch Block as well as a reduced ejection fraction and prolonged QRS duration. Yet, it is still not well understood why 30 to 40 % of CRT recipients do not respond. Echocardiography, due to its portability and ease-of-use, is the most frequently used imaging modality in clinical cardiology. In this dissertation, we assess the clinical performance of Electromechanical Wave Imaging (EWI) as a high frame rate ultrasound-based functional modality that can non-invasively map the electromechanical activation of the heart, i.e., the transient deformations immediately following the electrical activation. The objective of this dissertation is to demonstrate the potential clinical value of EWI for both arrhythmia detection and CRT characterization applications. The first step in translating EWI to the clinic was ensuring that the technique could reli- ably and reproducibly measure the electromechanical activation sequence independently of the probe angle and imaging view in healthy human volunteers (n=7). This dissertation then demonstrated the accuracy of EWI for localizing a variety of ventricular and atrial arrhythmias (accessory pathways in Wolff-Parkinson-White (WPW) syndrome, premature ventricular contractions, focal atrial tachycardia and macro-reentrant atrial flutter) in pediatric (n=14) and adult (n=55) patients prior to catheter ablation more accurately than 12-lead ECG predictions, as validated against electroanatomical mapping. Additionally, 3D-rendered EWI isochrones were illustrated to be capable of significantly distinguishing different biventricular pacing conditions (p≤0.05) with the RWAT and LWAT metrics, assessing the ventricular dyssynchrony change in heart failure patients (n=16) undergoing CRT, and visualizing it in 3D. EWI also provided quantification of %𝘙𝘔𝘓𝘝 in CRT patients (n=38): the amount of left-ventricular resynchronized myocardium, which was found to be a reliable response predictor at 3-, 6-, or 9-month clinical follow-up through its post-CRT values by significantly identifying super-responders from non-responders within 24 hours of implantation (p≤0.05). Furthermore, 3D-rendered isochrones successfully characterized the ventricular activation resulting from His Bundle pacing for the first time (n=4), which was undistinguishable from true physiological activation in sinus rhythm healthy volunteers with the EWI-based activation time distribution dispersion metric. The dispersion was, however, reported to significantly discriminate novel His pacing from other more conventional biventricular pacing schemes (p≤0.01). Finally, we developed and optimized a fully automated zero-crossing algorithm towards a faster, more robust and less observer dependent EWI isochrone generation process. The support vector machine (SVM) and Random Forest machine learning models were both shown capable of successfully identifying the accessory pathway in WPW patients and the pacing electrode location in paced canines. Nevertheless, the best performing algorithm was hereby proven to be the Random Forest classifier with n=200 trees with a precision rising to 97%, and a predictivity that was not impacted by the type of testing dataset it was applied to (human or canine). Overall, in this dissertation, we established the clinical potential of EWI as a viable assisting visual feedback tool, that could not only be used for diagnosis and treatment planning prior to surgical procedures, but also for monitoring during, and assessing long-term resolution of arrhythmia after catheter ablation or heart failure after a CRT implant.

We develop a composite multiphysics model of excitation-contraction coupling for a rat ventricular myocyte under voltage clamp (VC) conditions to: (1) probe mechanisms underlying the response to Ca2+-perturbation; (2) investigate the factors influencing its electromechanical response; and (3) examine its rate-dependent behavior (particularly the force-frequency response (FFR)). Motivation for the study was to pinpoint key control variables influencing calcium-induced calcium-release (CICR) and examine its role in the context of a physiological control system regulating cytosolic Ca2+ concentration and hence the cardiac contractile response. Our cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments. The model incorporates frequency-dependent calmodulin (CaM) mediated spatially heterogenous interaction of calcineurin (CaN) and Ca2+/calmodulin-dependent protein kinase-II (CaMKII) with their principal targets and accounts for rate-dependent, cyclic adenosine monophosphate (cAMP)-mediated up-regulation. We also incorporate a biophysical model for cardiac contractile mechanics to study the factors influencing force response. The model reproduces measured VC data published by several laboratories, and generates graded Ca2+-release with high Ca2+ gain by achieving negative feedback control and Ca2+-homeostasis. We examine the dependence of cellular contractile response on: (1) the amount of activator Ca2+ available; (2) the type of mechanical load applied; (3) temperature (22 to 38ºC); and (4) myofilament Ca2+ sensitivity. We demonstrate contraction-relaxation coupling over a wide range of physiological perturbations. Our model reproduces positive peak FFR observed in rat ventricular myocytes and provides quantitative insight into the underlying rate-dependence of CICR. The role of Ca2+ regulating mechanisms are examined in handling induced Ca2+-perturbations using a rigorous cellular Ca2+ balance. Extensive testing of the composite model elucidates the importance of various direct and indirect modulatory influences on the cellular twitch-response with wide agreement with measured data on all accounts. We identify cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of Ca2+-trigger current (ICaL) as the key mechanisms underlying the aforementioned positive FFR. Our model provides biophysically-based explanations of phenomena associated with CICR and provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility.