Novel cardiovascular magnetic resonance phenotyping of the myocardium

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

Doctor of Philosophy

dissertationMyocardial microstructure plays an important role in sustaining the orchestrated beating motion of the heart. Several microstructural components, including myocytes and auxiliary cells, extracellular space, and blood vessels provide the infrastructure for normal heart function, including excitation propagation, myocyte contraction, delivery of oxygen and nutrients, and removing byproduct wastes. Cardiac diseases cause deleterious changes to some or all of these microstructural components in the detrimental process of cardiac remodeling. Since heart failure is among the leading causes of death in the world, new and novel tools to noninvasively characterize heart microstructure are needed for monitoring and staging of cardiac disease. In this regards, diffusion magnetic resonance imaging (MRI) provides a promising framework to probe and quantify tissue microstructure without the need for exogenous contrast agent. As diffusion in 3-dimensional space is characterized by the diffusion tensor, MR diffusion tensor imaging (DTI) is being used to noninvasively measure anisotropic diffusion, and thus the magnitude and spatial orientation of microstructural organization of tissues, including the heart. However, even though in vivo cardiac DTI has become more clinically available, to date the origin and behavior of different microstructural components on the measured DTI signal remain to be explicitly specified. The presented studies in this work demonstrate that DTI can be used as a noninvasive and contrast-free imaging modality to characterize myocyte size and density, extracellular collagen content, and the directional magnitude of blood flow. The identified applications are expected to provide metrics to enable physicians to detect, quantify, and stage different microstructural components during progression of cardiac disease

Clinical translation of three-dimensional scar, diffusion tensor imaging, four-dimensional flow, and quantitative perfusion in cardiac MRI: a comprehensive review

Cardiovascular magnetic resonance (CMR) imaging is a versatile tool that has established itself as the reference method for functional assessment and tissue characterisation. CMR helps to diagnose, monitor disease course and sub-phenotype disease states. Several emerging CMR methods have the potential to offer a personalised medicine approach to treatment. CMR tissue characterisation is used to assess myocardial oedema, inflammation or thrombus in various disease conditions. CMR derived scar maps have the potential to inform ablation therapy—both in atrial and ventricular arrhythmias. Quantitative CMR is pushing boundaries with motion corrections in tissue characterisation and first-pass perfusion. Advanced tissue characterisation by imaging the myocardial fibre orientation using diffusion tensor imaging (DTI), has also demonstrated novel insights in patients with cardiomyopathies. Enhanced flow assessment using four-dimensional flow (4D flow) CMR, where time is the fourth dimension, allows quantification of transvalvular flow to a high degree of accuracy for all four-valves within the same cardiac cycle. This review discusses these emerging methods and others in detail and gives the reader a foresight of how CMR will evolve into a powerful clinical tool in offering a precision medicine approach to treatment, diagnosis, and detection of disease

The year in cardiology: imaging. The year in cardiology 2019.

No abstract available

Review of Journal of Cardiovascular Magnetic Resonance 2015

There were 116 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2015, which is a 14 % increase on the 102 articles published in 2014. The quality of the submissions continues to increase. The 2015 JCMR Impact Factor (which is published in June 2016) rose to 5.75 from 4.72 for 2014 (as published in June 2015), which is the highest impact factor ever recorded for JCMR. The 2015 impact factor means that the JCMR papers that were published in 2013 and 2014 were cited on average 5.75 times in 2015. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal's impact over the last 5 years has been impressive. Our acceptance rate is <25 % and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication

Review of Journal of Cardiovascular Magnetic Resonance 2014

There were 102 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2014, which is a 6 % decrease on the 109 articles published in 2013. The quality of the submissions continues to increase. The 2013 JCMR Impact Factor (which is published in June 2014) fell to 4.72 from 5.11 for 2012 (as published in June 2013). The 2013 impact factor means that the JCMR papers that were published in 2011 and 2012 were cited on average 4.72 times in 2013. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal’s impact over the last 5 years has been impressive. Our acceptance rate is <25 % and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication

Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy

A Novel Composite Material-based Computational Model for Left Ventricle Biomechanics Simulation

To model cardiac mechanics effectively, various mechanical characteristics of cardiac muscle tissue including anisotropy, hyperelasticity, and tissue active contraction characteristics must be considered. Some of these features cannot be implemented using commercial finite element (FE) solvers unless additional custom-developed computer codes/subroutines are appended. Such codes/subroutines are unavailable for the research community. Accordingly, the overarching objective of this research is to develop a novel LV mechanics model which is implementable in commercial FE solvers and can be used effectively within inverse FE frameworks towards cardiac disease diagnosis and therapy. This was broken down into a number of objectives. The first objective is to develop a novel cardiac tissue mechanical model. This model was constructed of microstructural cardiac tissue constituents while their associated volume contributions and mechanical properties were incorporated into the model. These constituents were organized in small FE tissue specimen models consistent with the normal/pathological cardiac tissue microstructure. In silico biaxial/uniaxial mechanical tests were conducted on the specimen models and corresponding stress-strain data were validated by comparing them with cardiac tissue data reported in the literature. Another objective of this research is developing a novel FE-based mechanical model of the LV which is fully implementable using commercial FE solvers without requiring further coding, potentially leading to a computationally efficient model which is easily adaptable to diverse pathological conditions. This was achieved through considering a novel composite material model of the cardiac tissue while all aspects of the cardiac mechanics including hyperelasticity, anisotropy, and active tissue responses were preserved. The model was applied to an in silico geometry of a canine LV under both normal and pathological conditions and systolic/diastolic responses of the model were compared with corresponding data of other LV mechanical models and LV contraction measurements. To test the suitability of the proposed cardiac model for FE inversion-based algorithms, the model was utilized for LV diastolic mechanical simulation to estimate the tissue stiffness and blood pressure using an ad-hoc optimization scheme. This led to reasonable tissue stiffness and blood pressure values falling within the range of LV measurements of healthy subjects, confirming the efficacy of this model for inversion-based diagnosis applications

High-Resolution Whole-Heart Imaging and Modeling for Studying Cardiac Arrhythmia

Cardiac arrhythmia is a life-threatening heart rhythm disorder affecting millions of people worldwide. The underlying structure of the heart plays an important role in cardiac activity and could promote rhythm disorders. Accurate knowledge of whole-heart cardiac geometry and microstructure in normal and disease hearts is essential for a complete understanding of the mechanisms of arrhythmias. This dissertation presents novel structural data at the whole-heart level aimed at advancing knowledge of cardiac structure in normal and infarcted hearts, and at constructing whole-heart computational models. A 3D diffusion tensor MRI (DTMRI) technique was implemented on a clinical scanner to image intact large animal and human hearts with high image quality and spatial resolution ex vivo. This method was first applied to reconstruct the 3D myofiber organization in 8 human atria nondestructively and at submillimeter resolution. The findings showed that the main features of atrial anatomy are mostly preserved across subjects despite variability in the exact location and orientation of the bundles. Further, we were able to cluster, visualize, and characterize the distinct major bundles in the human atria. Quantitative analysis of the fiber angles across the atrial wall revealed that the transmural fiber angle distribution is heterogeneous throughout the atria. We next studied microstructural remodeling in infarcted porcine and human hearts by combining DTMRI with high-resolution Late Gadolinium Enhancement imaging. This enabled us to provide reconstructions of both fiber architecture and scar distribution in infarcted hearts with an unprecedented level of detail, and to systematically quantify the transmural pattern of diffusion eigenvector orientation. Our results demonstrated that the fiber orientation is generally preserved inside the scar but at a higher transmural gradient of inclination angle. Lastly, we employed the obtained data to generate whole-heart computational models of infarcted hearts with detailed scar geometry and subject-specific fiber orientation. We used these models in simulations to investigate the contribution of the infarct microarchitecture to ventricular tachycardia. The simulation results showed that the reentry circuits traverse thin viable tissues with complex geometries located inside of the infarct. The high resolution of the images enabled 3D reconstruction and characterization of such structures