109 research outputs found

    Measurement of left ventricular deformation using 3D echocardiography

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    Bakgrunn: 3D speckle tracking ekkokardiografi (STE) er en hjerteultralydmetode som gir mulighet for måling av deformasjonsparametere, som strain, rotasjon, tvist og torsjon. Den største begrensningen for 3D STE er lav tids- og romlig oppløsning. Økes den ene oppløsingen vil den andre bli redusert. I tillegg vil andre faktorer som antall flettede bilder, sektorstørrelse og dybde påvirke begge oppløsningene. Denne avhandlingen har hatt som mål å finne tilstander og opptaksinnstillinger for å optimalisere nøyaktigheten til 3D STE-parametere i et kontrollert miljø. Videre har det vært som mål å finne regional deformasjon fra 3D STE i en klinisk studie på pasienter med aortaklaffestenose (AS) ved bruk av optimaliserte innstillinger. Materiale og metode: Studie 1 og 2 utforsket nøyaktigheten til 3D STE ved bruk av et in vitro-oppsett med et fantom av venstre ventrikkel. Studie 1 sammenlignet 3D STE strain mot sonomikromertri som gullstandard i longitudinell, sirkumferensiell og radiell retning. Ved å bruke et annet fantom i studie 2 ble 3D STE tvist sammenlignet mot sonomikrometri tvist for å finne nøyaktigheten til 3D STE tvistmålinger. Studie 3 inkluderte 85 pasienter med variabel grad av AS i en tverrsnittstudie. 3D ekkokardiografi ble utført og 3D STE-parametere ble sammenlignet mellom grupper av pasienter med mild, moderat og alvorlig AS. Resultater: Studie 1 fant godt samsvar mellom 3D STE og sonomikrometri med optimalt volum rate på 36,6 volumer per sekund (VPS) ved bruk av 6 sammenflettede bilder. I studie 2 hadde 3D STE godt samsvar ved bruk av både 4 og 6 sammenflettede bilder med volum rater på henholdsvis 20,3 og 17,1 VPS. Studie 3 fant lavere global longitudinal strain i pasienter med alvorlig AS sammenlignet med mild AS. Basal og midtre longitudinal strain var også lavere i alvorlig sammenlignet med mild AS. Apikal-basal ratio var høyere for moderat i forhold til mild AS. Maks apikal-basal tvist var høyere hos pasienter med alvorlig sammenlignet med mild og moderat AS. Konklusjon: Måling av venstre ventrikkelfunksjon med 3D STE er mest nøyaktig med volum rater < 40 VPS. Høy romlig oppløsning virker å være mer viktig enn tidsoppløsning. Pasienter med alvorlig AS har lavere global, basal og midtre longitudinal strain enn pasienter med mild AS, ved bruk av 3D STE. De har også høyere tvist enn mild og moderat AS. Områder som involverer apeks, har høyere spredning av data og har antagelig lavere nøyaktighet ved bruk av 3D STE.Background: 3D speckle tracking echocardiography (STE) enables measurement of multiple parameters of deformation, such as strain, rotation, twist and torsion. The main limitation of 3D STE is low temporal and spatial resolution. Increasing resolution in time will decrease resolution in space, and vice versa. In addition, other factors such as number of stitched images, sector size and depth, influence the resolution. This thesis aimed to find conditions and acquisition settings to optimize accuracy for 3D STE parameters in a controlled in vitro environment. Secondly, it aimed to evaluate regional deformation by 3D STE in a clinical study on patients with aortic valve stenosis (AS) using optimized settings. Materials and methods: Study 1 and 2 explored the accuracy of 3D STE using an in vitro setup with a left ventricle (LV) phantom. Study 1 compared 3D STE strain to strain by sonomicrometry as the gold standard. Measurements were compared in both longitudinal, circumferential and radial direction. Using a different twisting phantom in study 2, 3D STE twist was compared to twist by sonomicrometry to evaluate the accuracy of 3D STE twist. Study 3 was a cross-sectional analysis of 85 patients with variable degree of AS in a cross-sectional study. 3D echocardiography was done, and 3D STE parameters were compared between groups of patients with mild, moderate and severe AS. Results: Study 1 found 3D STE strain to have good agreement with sonomicrometry. Optimal acquisition settings were found to be volume rate 36.6 volumes per second (VPS) obtained by 6 stitched images. Study 2 found 3D STE twist to have good agreement with sonomicrometry when using both 4 and 6 stitched images with volume rates 20.3 and 17.1 VPS, respectively. Study 3 found global longitudinal strain to be lower in patients with severe AS compared to those with mild AS. Basal and mid longitudinal strains were also lower in severe AS than in mild AS. Apical basal ratio was higher for moderate than mild AS. Peak apical-basal twist was higher in patients with severe AS than in those with mild and moderate AS. Conclusion: Assessment of LV function by 3D STE is most accurate at volume rates < 40 VPS. High spatial resolution seems to be more important than temporal resolution. Patients with severe AS have lower global, as well as lower regional basal and mid longitudinal strain compared to patients with mild AS, assessed with 3D STE. They also have higher twist than mild and moderate AS. Segments involving the apex have high dispersion and probably lower accuracy in 3D STE.Doktorgradsavhandlin

    The molecular genetics of familial cardiomyopathy

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    Introduction The cardiomyopathies are responsible for approximately 5.9 of 100,000 deaths in the general global population and in sub-Saharan Africa (SSA), these myocardial diseases are observed in 21.4% of patients with heart failure. The precise etiology of the cardiomyopathies is currently not well known and through our research we aim to contribute to the genetic landscape and bridge the gaps in knowledge for the different cardiomyopathies as SSA could provide some very important insights into the cardiomyopathies and identify other possible disease mechanisms. Methods Through next generation sequencing techniques such as whole exome sequencing and targeted resequencing we studied three South African families with severe cardiomyopathy. Clinical diagnosis and recruitment of cardiomyopathy patients into the study was done at Groote Schuur Hospital, Cape Town by a panel of experts. Next generation sequencing data was analysed and filtered through various stringent criteria and the final list of variants were validated through Sanger sequencing. Results In the first multi-generational family with severe dilated cardiomyopathy (DCM) (DCM 334), we identified a pathogenic DMPK c.1067C>T(p.P356L) variant in the proband and her affected father. We also screened a cohort of 542 cardiomyopathy probands though Sanger sequencing of the DMPK gene and identified the DMPK c.1477C>T(p.R493C) variant as a variant of unknown significance. We then investigated a three-generation family with four affected family members who were also affected with severe DCM (DCM343). We used whole exome sequencing and identified the pathogenic BAG3 c.925C>T (p.R309Ter) variant as the cause of disease within this family. Viral infection, anti-hypertensive medication and genetic modifiers in RYR1 and NEB contributed to the variable phenotype among the individuals with the BAG3 variant. Through targeted resequencing we also identified the same pathogenic BAG3 variant in 2 of the 634 cardiomyopathy probands screened. In the third family, we investigated a South African family affected with severe arrhythmogenic cardiomyopathy (ACM). We used whole exome sequencing and targeted resequencing in combination and identified the pathogenic PKP2 c.2197_2202InsGdelCACACC (p.H733Afs*8) as the cause of disease in the proband and his father. We also present evidence of the ALPK3 c.2701C>T(p.Q901Ter) variant modifying the phenotypic manifestation which correlates with the variable penetrance that is seen among ACM families. Conclusion Through this project, we have identified many firsts. To the best of our knowledge, we are the first to show that DMPK is associated with primary DCM in severely affected young patients. As a first for South Africa, we not only identified the pathogenic BAG3 variant in a family with severe DCM, but we also identified the same variant in two additional probands, raising the possibility of a founder effect. In the third and final family with ACM, we identified the pathogenic PKP2 variant as the cause of disease within this family with the novel ALPK3 variant acting as a possible modifier. Our research has added to what is currently known about the cardiomyopathies in Africa but there is still much work to be done as we believe we have just scratched the tip of the iceberg

    Mathematical modelling of myocardial perfusion: coronary flow and myocardial mechanics

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    Coronary artery disease (CAD) is a condition characterised by the narrowing or blockage of the major blood vessels that supply blood to the heart muscle. This can cause insufficient myocardial perfusion to the heart and deficient cardiac outputs, leading to the possibility of heart failure. CAD is one of the leading causes of morbidity and mortality worldwide. Early and accurate diagnosis and treatment of CAD are essential to minimise the risk of complications, including heart attack or heart failure. In cardiovascular research, computational modelling of coronary circulation is proving to be a valuable tool for gaining insights and information. It enables researchers to isolate the effects of various physiological and pathological conditions on the coronary circulation. Thus, this thesis aimed to develop computational models of one dimensional (1D) coronary flow and three-dimensional (3D) heart. Both models included detailed geometric information tosimulate and predict physiologically realistic results. A one- way coupling of the coronary flow model and the heart model was achieved and produced physiologically accurate myocardial perfusion. Specifically, we first investigated the effect of intramyocardial pressure (IMP) on coronary flow and developed a 1D finite difference coronary flow model. A coronary network based on experimental data was constructed to simulate coronary flow along the complete path of the coronary vasculature. Utilising an assumed aortic pressure, right atrial pressure, and IMP, our simulated coronary pressure and flow rates were in good agreement with published experimental data. It was observed that the majority of the coronary arterial flow on the left side occurs during diastole, while the flow slows down or even reverses during systole. Secondly, we developed a 3D finite element model of the left ventricle (LV) to obtain a more realistic IMP. The LV model was constructed from a patient-specific geometry. The simulated pressure and volume of the LV cavity in repeated cardiac cycles, as well as the ejection fraction, were all within published physiological ranges. We further analysed the stress distributions within the LV wall. Thirdly, a brief review of experimental IMP, as well as calculations of IMP from lumped parameter models and 3D heart models, were presented. Through analysis, we determined a formula for calculating IMP from our 3D LV model. Additionally, we proposed an assignment scheme of the epicardial coronary arteries to the 17 segments of the LV wall recommended by the American Heart Association. Based on the assignment, we devised the one-way coupling framework between the coronary flow model and the LV model to investigate myocardial perfusion. We further developed a bi-ventricular model to investigate the effect of pulmonary regurgitation (PR) on cardiac function. The model provided a computational approach for exploring the influence of PR on right ventricle (RV) dilation and the interaction between LV and RV. Our simulated RV end-diastolic volumes under varying degrees ofPR were comparable with published magnetic resonance imaging data. Moreover, from the long-axis and short-axis views of the bi-ventricular geometry, we observed clearly the motion of the interventricular septum from the baseline case to the severe PR case. This bi-ventricular model was intended to further couple with the coronary flow model to investigate the interaction of right coronary arterial flow and left coronary arterial flow. However, due to time constraints, this has not yet been undertaken. The computational models of the coronary flow and heart developed in this thesis exhibit promising capabilities for providing physiologically accurate predictions of coronary flow and myocardial mechanics. Further application of these models has the potential to deepen our understanding of the underlying mechanisms in physiological coronary flow and various CAD

    Pacing with restoration of respiratory sinus arrhythmia improved cardiac contractility and the left ventricular output: a translational study

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    Introduction: Respiratory sinus arrhythmia (RSA) is a prognostic value for patients with heart failure and is defined as a beat-to-beat variation of the timing between the heart beats. Patients with heart failure or patients with permanent cardiac pacing might benefit from restoration of RSA. The aim of this translational, proof-of-principle study was to evaluate the effect of pacing with or without restored RSAon parameters of LV cardiac contractility and the cardiac output

    Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

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    [ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI
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