329 research outputs found

    Cardiac multi-scale investigation of the right and left ventricle ex vivo: a review

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    The heart is a complex multi-scale system composed of components integrated at the subcellular, cellular, tissue and organ levels. The myocytes, the contractile elements of the heart, form a complex three-dimensional (3D) network which enables propagation of the electrical signal that triggers the contraction to efficiently pump blood towards the whole body. Cardiovascular diseases (CVDs), a major cause of mortality in developed countries, often lead to cardiovascular remodeling affecting cardiac structure and function at all scales, from myocytes and their surrounding collagen matrix to the 3D organization of the whole heart. As yet, there is no consensus as to how the myocytes are arranged and packed within their connective tissue matrix, nor how best to image them at multiple scales. Cardiovascular imaging is routinely used to investigate cardiac structure and function as well as for the evaluation of cardiac remodeling in CVDs. For a complete understanding of the relationship between structural remodeling and cardiac dysfunction in CVDs, multi-scale imaging approaches are necessary to achieve a detailed description of ventricular architecture along with cardiac function. In this context, ventricular architecture has been extensively studied using a wide variety of imaging techniques: ultrasound (US), optical coherence tomography (OCT), microscopy (confocal, episcopic, light sheet, polarized light), magnetic resonance imaging (MRI), micro-computed tomography (micro-CT) and, more recently, synchrotron X-ray phase contrast imaging (SR X-PCI). Each of these techniques have their own set of strengths and weaknesses, relating to sample size, preparation, resolution, 2D/3D capabilities, use of contrast agents and possibility of performing together with in vivo studies. Therefore, the combination of different imaging techniques to investigate the same sample, thus taking advantage of the strengths of each method, could help us to extract the maximum information about ventricular architecture and function. In this review, we provide an overview of available and emerging cardiovascular imaging techniques for assessing myocardial architecture ex vivo and discuss their utility in being able to quantify cardiac remodeling, in CVDs, from myocyte to whole organ

    Micro-computed tomography for high resolution soft tissue imaging; applications in the normal and failing heart

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    The normal structure and function of the heart, the common pathological changes that cause abnormal function and the interventions proposed to improve or restore its function are fundamentally based on cardiac anatomy. Therefore in all these areas a detailed and accurate understanding of 3D structure is essential. However there is still disparity over some aspects of the form and function of the healthy heart. Furthermore, in heart failure (HF) the transition from compensated to decompensated HF is poorly understood, and details of ventricular, and particularly atrial, remodelling and their effects on cardiac function are yet to be fully elucidated. In addition little is known on how the 3D morphology of the cardiac conduction system is affected in disease, and further knowledge is required on the structural substrates for arrhythmogenesis associated with HF. Here we have developed contrast enhanced micro-CT for soft tissue imaging, allowing non-invasive high resolution (~5 µm attainable) differentiation of multiple soft tissue types including; muscle, connective tissue and fat. Micro-CT was optimised for imaging of whole intact mammalian hearts and from these data we reveal novel morphological and anatomical detail in healthy hearts and in hearts after experimental HF (volume and pressure overload). Remodelling of the myocardium in HF was dramatic with significant hypertrophy and dilatation observed in both atria and ventricles. The atria showed a 67% increase in myocardial volume, with the left atrium showing a 93% increase. The pectinate muscle: wall thickness ratio was significantly increased in both atria (p

    Novel cardiovascular magnetic resonance phenotyping of the myocardium

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    INTRODUCTION Left ventricular (LV) microstructure is unique, composed of a winding helical pattern of myocytes and rotating aggregations of myocytes called sheetlets. Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease characterised by left ventricular hypertrophy (LVH), however the link between LVH and underlying microstructural aberration is poorly understood. In vivo cardiovascular diffusion tensor imaging (cDTI) is a novel cardiovascular MRI (CMR) technique, capable of characterising LV microstructural dynamics non-invasively. In vivo cDTI may therefore improve our understanding microstructural-functional relationships in health and disease. METHODS AND RESULTS The monopolar diffusion weighted stimulated echo acquisition mode (DW-STEAM) sequence was evaluated for in vivo cDTI acquisitions at 3Tesla, in healthy volunteers (HV), patients with hypertensive LVH, and HCM patients. Results were contextualised in relation to extensively explored technical limitations. cDTI parameters demonstrated good intra-centre reproducibility in HCM, and good inter-centre reproducibility in HV. In all subjects, cDTI was able to depict the winding helical pattern of myocyte orientation known from histology, and the transmural rate of change in myocyte orientation was dependent on LV size and thickness. In HV, comparison of cDTI parameters between systole and diastole revealed an increase in transmural gradient, combined with a significant re-orientation of sheetlet angle. In contrast, in HCM, myocyte gradient increased between phases, however sheetlet angulation retained a systolic-like orientation in both phases. Combined analysis with hypertensive patients revealed a proportional decrease in sheetlet mobility with increasing LVH. CONCLUSION In vivo DW-STEAM cDTI can characterise LV microstructural dynamics non-invasively. The transmural rate of change in myocyte angulation is dependent on LV size and wall thickness, however inter phase changes in myocyte orientation are unaffected by LVH. In contrast, sheetlet dynamics demonstrate increasing dysfunction, in proportion to the degree of LVH. Resolving technical limitations is key to advancing this technique, and improving the understanding of the role of microstructural abnormalities in cardiovascular disease expression.Open Acces

    Analysis of myocardial contractility with magnetic resonance

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    Heart failure has considerable morbidity and poor prognosis. An understanding of the underlying mechanics governing myocardial contraction is a prerequisite for interpreting and predicting changes induced by heart disease. Gross changes in contractile behaviour of the myocardium are readily detected with existing techniques. For more subtle changes during early stages of cardiac dysfunction, however, it requires a sensitive method for measuring, as well as a precise criterion for quantifying, normal and impaired myocardial function. Cardiovascular Magnetic Resonance (CMR) imaging is emerging as an important clinical tool because of its safety, versatility, and the high quality images it produces that allow accurate and reproducible quantification of cardiac structure and function. Traditional CMR approaches for measuring contractility rely on tagging of the myocardium with fiducial markers and require a lengthy and often subjective dependant post-processing procedure. The aim of this research is to develop a new technique, which uses velocity as a marker for the visualisation and assessment of myocardial contractility. Two parallel approaches have been investigated for the assessment of myocardial velocity. The first of these is haimonic phase (HARP) imaging. HARP imaging allows direct derivation of myocardial velocity and strain without the need of further user interaction. We investigated the effect of respiration on the accuracy of the derived contractility, and assessed the clinical applicability and potential pitfalls of the technique by analysing results from a group of patients with hypertrophic cardiomyopathy. The second technique we have investigated is the direct measurement of myocardial velocity with phase contrast myocardial velocity mapping. The imaging sequence used employs effective blood saturation for reducing flow induced phase errors within the myocardium. View sharing was used to improve the temporal resolution, which permitted acquisition of 3D velocity information throughout the cardiac cycle in a single breath-hold, enabling a comprehensive assessment of strain rate of the left ventricle. One key factor that affects the derivation of myocardial contractility based on myocardial velocity is the practical inconsistency of the velocity data. A novel iterative optimisation scheme by incorporating the incompressibility constraint was developed for the restoration of myocardial velocity data. The method allowed accurate assessment of both in-plane and through-plan strain rates, as demonstrated with both synthetic and in vivo data acquired from normal subjects and ischaemic patients. To further enhance the clinical potential of the technique and facilitate the visual assessment of contractile abnormality with myocardial velocity mapping, a complementary analysis framework, named Virtual Tagging, has been developed. The method used velocity data in all directions combined with a finite element mesh incorporating geometrical and physical constraints. The Virtual Tagging framewoik allowed velocity measurements to be used for calculating strain distribution within the 3D volume. It also permitted easy visualisation of the displacement of the tissue, akin to traditional CMR tagging. Detailed validation of the technique is provided, which involves both numerical simulation and in vitro phantom experiments. The main contribution of this thesis is in the improvement of the effectiveness and quality of quantitative myocardial contractility analysis from both sequence design and medical image computing perspectives. It is aimed at providing a sensitive means of detecting subtle as well as gross changes in contractile behaviour of the myocardium. The study is expected to provide a clinically viable platform for functional correlation with other functional measures such as myocardial perfusion and diffusion, and to serve as an aid for further understanding of the links between intrinsicOpen acces

    Doctor of Philosophy

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    dissertationIn this thesis I present novel findings of microstructural remodeling that occurs during dyssynchronous heart failure (DHF) and the ability for cardiac resynchronization therapy (CRT) to reverse this remodeling. DHF is an advanced disease state that occurs in a large portion of patients suffering from heart failure. Mechanical dyssynchrony between the left and right ventricles of the heart, the hallmark of DHF, results in significantly increased heterogeneity of stress in the cardiac wall. DHF severely limits cardiac performance, decreasing quality of life and increasing mortality. The main therapy for treating DHF is CRT, a therapy in which mechanical synchrony is restored to the ventricles via electrical pacing. The success of CRT varies widely. Scientific knowledge surrounding DHF and CRT is surprisingly sparse for how widespread the disease and therapy are. A better understanding of the subcellular structure and function altered during DHF will improve our understanding of the disease and potentially help develop novel therapies and even lead to development of assays capable of better predicting success of current therapies. Here we use confocal microscopy to explore protein distributions within isolated cardiomyocytes and intact tissue, Ca2+ handling during activation and relaxation of stimulated cardiomyocytes, and to develop a method for quantifying strain in 2D image sequences of contracting cardiomyocytes at an unprecedented spatiotemporal resolution. Specifically I will demonstrate that ?-actinin, the protein comprising the majority of the sarcomeric Z-disk, is significantly altered during DHF and that CRT is able to partially reverse this remodeling. I will then present findings on remodeling of the transverse tubular system and associated ryanodine receptor clusters, both crucial components of excitation-contraction coupling. In particular, I will show that these structures exhibit subcellular heterogeneity during DHF, affecting excitation-contraction coupling. This heterogeneity is reduced after CRT, indicating previously unknown capabilities of restoration. Finally, I will present a novel method to characterize strain within contracting cardiomyocytes. This method expands on previous methods by providing a regional 2D strain tensor at unprecedented spatiotemporal resolution, allowing more accurate description of the mechanical properties of the cell. Together, this work makes a significant contribution to the understanding of DHF and CRT

    Calcium Remodeling through Different Signaling Pathways in Heart Failure: Arrhythmogenesis Studies of Pyk2, Dystrophin, and β-adrenergic Receptor Signaling

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    Heart failure is a common clinical syndrome that ensues when the heart is no longer able to generate sufficient cardiac output to meet the demands of the body. It is one of the leading causes of death worldwide but with limited and non-ideal therapies at the moment. One reason behind this may be the complexity of significant alterations in multiple signaling pathways and concomitant structural and functional remodeling, especially Ca handling. Ca is critical in both the electrical and mechanical properties of cardiac myoctyes, and much is known about ionic currents and the normal excitation-contraction coupling process. In heart failure, distinct impaired signaling pathways induce significant alterations in how cardiac Ca handling is regulated. These alterations either directly cause certain arrhythmias or facilitate arrhythmias by association with electrical remodeling. The goal of this dissertation was to investigate the mechanisms of calcium remodeling through different signaling pathways in heart failure, and mechanisms on how the intricate and dynamic interactions between Ca handling and signaling pathways impairment facilitate arrhythmias in heart failure. To achieve this goal, a dual optical mapping system was designed to investigate electrical activity and Ca transient simultaneously. High spatio-temporal resolution mapping allows for quantifying conduction, repolarization and Ca cycling, especially on the interactions between action potential and Ca handling. In this dissertation, I investigated Ca remodeling in three different signaling pathways: stress activated signaling, cytoskeletal signaling and β adrenergic receptor signaling pathway. Proline-rich tyrosine kinase 2: Pyk2) is a non-receptor protein kinase regulated by intracellular Ca. It mediates a typical stress activated signaling pathways along with c-Src, P38 MAPK and regulates a broad range of key biological responses. By optically mapping the genetically engineered mouse model: Pyk2 knockout, I detected a protective role of Pyk2 with respect to ventricular tachyarrhythmia during parasympathetic stimulation by regulation of gene expression related to calcium handling. The mdx mouse model was introduced in the investigation of cytoskeletal signaling pathway. mdx mice is a common model for Duchenne muscular dystrophy, which is a clinical syndrome resulted from recessive of dystrophin and eventually develops into heart failure. The project suggested the association of mechanical stimulation and deficiency of dystrophin account for the cardiac mechanical defects and resulting Ca mishandling, but not either of the two above-mentioned entities alone. Ca mishandling leads to Ca cycling dispersion, which facilitates generation of arrhythmias. β Adrenergic receptor signaling pathway was investigated on explanted donor and failing human hearts. Distinct β adrenergic receptor subtypes were found to regulate remodeling differently. The association between remodeling of action potential and Ca transient provides crucial arrhythmic drivers and substrate in heart failure

    Development of novel magnetic resonance methods for advanced parametric mapping of the right ventricle

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    The detection of diffuse fibrosis is of particular interest in congenital heart disease patients, including repaired Tetralogy of Fallot (rTOF), as clinical outcome is linked to the accurate identification of diffuse fibrosis. In the Left Ventricular (LV) myocardium native T1 mapping and Diffusion Tensor Cardiac Magnetic Resonance (DT-CMR) are promising approaches for detection of diffuse fibrosis. In the Right Ventricle (RV) current techniques are limited due to the thinner, mobile and complex shaped compact myocardium. This thesis describes technical development of RV tissue characterisation methods. An interleaved variable density spiral DT-CMR method was implemented on a clinical 3T scanner allowing both ex and in vivo imaging. A range of artefact corrections were implemented and tested (gradient timing delays, off-resonance and T2* corrections). The off- resonance and T2* corrections were evaluated using computational simulation demonstrating that for in vivo acquisitions, off-resonance correction is essential. For the first-time high-resolution Stimulated Echo Acquisition Mode (STEAM) DT-CMR data was acquired in both healthy and rTOF ex-vivo hearts using an interleaved spiral trajectory and was shown to outperform single-shot EPI methods. In vivo the first DT-CMR data was shown from the RV using both an EPI and an interleaved spiral sequence. Both sequences provided were reproducible in healthy volunteers. Results suggest that the RV conformation of cardiomyocytes differs from the known structure in the LV. A novel STEAM-SAturation-recovery Single-sHot Acquisition (SASHA) sequence allowed the acquisition of native T1 data in the RV. The excellent blood and fat suppression provided by STEAM is leveraged to eliminate partial fat and blood signal more effectively than Modified Look-Locker Imaging (MOLLI) sequences. STEAM-SASHA T1 was validated in a phantom showing more accurate results in the native myocardial T1 range than MOLLI. STEAM-SASHA demonstrated good reproducibility in healthy volunteers and initial promising results in a single rTOF patient.Open Acces

    Remodeling of fiber and laminar architecture of rat heart septum in a transitional normal state between pressure overload hypertrophy and failure

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    Congestive Heart Failure (CHF) is a major fatal disease today in the United States. The heart's function is a mechanical one. To diagnose and treat CHF effectively there is a need to understand at the microstructural level, the differences in the response of the myocardium to a change in its mechanical environment. Hence to assess growth and remodeling processes in the myocardium, the fiber and myolaminar structure of two groups of Dahl salt-sensitive rats were compared: low salt (LS) normal controls and a high salt (HS) group with hearts in "transitional eutrophy" defined by normal size and shape but in transition from pressure overload hypertrophy to dilated hypertrophy. To create the HS group with transitional eutrophy, we fed Dahl salt-sensitive rats, a sustained high salt diet from age 6 wks till sacrifice at age 11-13 wks. Such rats have a heart that transitions from too thick (pressure overload hypertrophy at about age 9 wks) to too thin (dilated hypertrophy at about age 15 wks to death) with a transitional period (age 11-13 wks) having normal size and shape. Fiber angles, sheet angles, number and thickness of sheets were measured in the septum at four transmural quarters (TQ1 to TQ4 with TQ1 being closest to LV and TQ4 closest to RV). A uniformity index was defined to characterize sheet angle dispersion. Upon comparison to LS controls, the HS group had normal size hearts with normal shape. However, there was a significant increase in the number of sheets, which corresponded with a significant decrease in the thickness of sheets in all quarters in HS group. Differences in fiber angles were significant in TQ1, TQ2, and TQ4 with fiber angles more positive in HS group. Differences in sheet angles and uniformity index were not significant. Despite having a normal size and shape, we found that hearts in a state of transitional eutrophy have a significantly different fiber and sheet morphology. The experimental data was used to develop a model that represents the path to failure that may be taken by the myolaminae when the heart is subjected to excessive pressure overload

    Doctor of Philosophy

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    dissertationImage-based biomechanics, particularly numerical modeling using subject-specific data obtained via imaging, has proven useful for elucidating several biomechanical processes, such as prediction of deformation due to external loads, applicable to both normal function and pathophysiology of various organs. As the field evolves towards applications that stretch the limits of imaging hardware and acquisition time, the information traditionally expected as input for numerical routines often becomes incomplete or ambiguous, and requires specific acquisition and processing strategies to ensure physical accuracy and compatibility with predictive mathematical modeling. These strategies, often derivatives or specializations of traditional mechanics, effectively extend the nominal capability of medical imaging hardware providing subject-specific information coupled with the option of using the results for predictive numerical simulations. This research deals with the development of tools for extracting mechanical measurements from a finite set of imaging data and finite element analysis in the context of constructing structural atlases of the heart, understanding the biomechanics of the venous vasculature, and right ventricular failure. The tools include: (1) application of Hyperelastic Warping image registration to displacement-encoded MRI for reconstructing absolute displacement fields, (2) combination of imaging and a material parameter identification approach to measure morphology, deformation, and mechanical properties of vascular tissue, and (3) extrapolation of diffusion tensor MRI acquired at a single time point for the prediction the structural changes across the cardiac cycle with mechanical simulations. Selected tools were then applied to evaluate structural changes in a reversible animal model for right ventricular failure due to pressure overload
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