Cardiac magnetic resonance assessment of diastolic dysfunction in acute coronary syndrome

Chest pain is an important presenting symptom. However, few cases of chest pain are diagnosed as acute coronary syndrome (ACS) in the acute setting. This results in frequent inappropriate discharge and major delay in treatment for patients with underlying ACS. The conventional methods of assessing ACS, which include electrocardiography and serological markers of infarct, can take time to manifest. Recent studies have investigated more sensitive and specific imaging modalities that can be used. Diastolic dysfunction occurs early following coronary artery occlusion and its detection is useful in confirming the diagnosis, risk stratification, and prognosis post-ACS. Cardiac magnetic resonance provides a single imaging modality for comprehensive evaluation of chest pain in the acute setting. In particular, cardiac magnetic resonance has many imaging techniques that assess diastolic dysfunction post-coronary artery occlusion. Techniques such as measurement of left atrial size, mitral inflow, and mitral annular and pulmonary vein flow velocities with phase-contrast imaging enable general assessment of ventricular diastolic function. More novel imaging techniques, such as T2-weighted imaging for oedema, T1 mapping, and myocardial tagging, allow early determination of regional diastolic dysfunction and oedema. These findings may correspond to specific infarcted arteries that may be used to tailor eventual percutaneous coronary artery intervention

Noninvasive Cardiac Flow Assessment Using High Speed Magnetic Resonance Fluid Motion Tracking

Cardiovascular diseases can be diagnosed by assessing abnormal flow behavior in the heart. We introduce, for the first time, a magnetic resonance imaging-based diagnostic that produces sectional flow maps of cardiac chambers, and presents cardiac analysis based on the flow information. Using steady-state free precession magnetic resonance images of blood, we demonstrate intensity contrast between asynchronous and synchronous proton spins. Turbulent blood flow in cardiac chambers contains asynchronous blood proton spins whose concentration affects the signal intensities that are registered onto the magnetic resonance images. Application of intensity flow tracking based on their non-uniform signal concentrations provides a flow field map of the blood motion. We verify this theory in a patient with an atrial septal defect whose chamber blood flow vortices vary in speed of rotation before and after septal occlusion. Based on the measurement of cardiac flow vorticity in our implementation, we establish a relationship between atrial vorticity and septal defect. The developed system has the potential to be used as a prognostic and investigative tool for assessment of cardiac abnormalities, and can be exploited in parallel to examining myocardial defects using steady-state free precession magnetic resonance images of the heart

Theory and Validation of Magnetic Resonance Fluid Motion Estimation Using Intensity Flow Data

15 p.Background Motion tracking based on spatial-temporal radio-frequency signals from the pixel representation of magnetic resonance (MR) imaging of a non-stationary fluid is able to provide two dimensional vector field maps. This supports the underlying fundamentals of magnetic resonance fluid motion estimation and generates a new methodology for flow measurement that is based on registration of nuclear signals from moving hydrogen nuclei in fluid. However, there is a need to validate the computational aspect of the approach by using velocity flow field data that we will assume as the true reference information or ground truth. Methodology/Principal Findings In this study, we create flow vectors based on an ideal analytical vortex, and generate artificial signal-motion image data to verify our computational approach. The analytical and computed flow fields are compared to provide an error estimate of our methodology. The comparison shows that the fluid motion estimation approach using simulated MR data is accurate and robust enough for flow field mapping. To verify our methodology, we have tested the computational configuration on magnetic resonance images of cardiac blood and proved that the theory of magnetic resonance fluid motion estimation can be applicable practically. Conclusions/Significance The results of this work will allow us to progress further in the investigation of fluid motion prediction based on imaging modalities that do not require velocity encoding. This article describes a novel theory of motion estimation based on magnetic resonating blood, which may be directly applied to cardiac flow imaging.Kelvin Kian Loong Wong, Richard Malcolm Kelso, Stephen Grant Worthley, Prashanthan Sanders, Jagannath Mazumdar, Derek Abbot

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Magnetic resonance imaging of atherosclerotic plaque / Stephen G. Worthley.

Includes a list of thesis related publications, reviews and thesis related abstracts, awards, book chapters and invited presentations (leaves vii-xii).Includes bibliographical references (leaves 179-234).xvii, 234 leaves : ill. (some col.) ; 30 cm.A systematic evaluation of magnetic resonance imaging and its use in the ex vivo and in vivo setting, in the aorta and coronary arteries in rabbit and porcine models, leading to the potential for human coronary atherosclerotic imaging.Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 200

Assessment of diastolic dysfunction in patients with acute coronary syndrome and preserved systolic function: comparison between Doppler transthoracic echocardiography and velocity-encoded cardiac magnetic resonance

Objectives: Transthoracic echocardiography (TTE) remains the mainstay diagnostic imaging tool for the assessment of diastolic dysfunction.However, velocity-encoded phase-contrast imaging permits evaluation with cardiac magnetic resonance (CMR) with excellent capabilities to assess blood flow and myocardial tissue motion. We evaluated the feasibility of measuring mitral blood flow, mitral annular velocity and pulmonary vein flow in assessing diastolic dysfunction in acute coronary syndrome (ACS) patients. Methods: Revascularized acute myocardial infarction patients with normal left ventricular (LV) systolic function on TTE were assessed by 1.5T CMR.Following acquisition of regular short-axis cine volumetry and 2-, 3- and 4-chamber views, we performed single-slice velocity-encoded phase-contrast imaging in short-axis plane at the level of the mitral leaflet tips and in a plane perpendicular to a pulmonary vein. Early, late diastolic mitral inflow velocities, peak systolic, diastolic pulmonary vein velocities and myocardial annular velocities were determined. These were then compared to comparable TTE parameters. Results: Fourty-six patients were analyzed. Mean LVEF was 61.1±8.9%. Peak E and A velocities underestimated by CMR, E/A ratio showed a significant correlation with TTE, R2 0.51. Peak S and D velocities also underestimated, S/D ratio significantly correlated with TTE, R2 0.58. Paradoxically, E’ is overestimated by CMR, with lower E/E’ ratio but still significantly correlated with TTE, R2 0.55. Bland-Altman analysis demonstrated excellent agreement with excellent reproducibility. Conclusion: CMR evaluation of diastolic dysfunction post-ACS has significant correlation with TTE. Although velocity-encoded phase-contrast imaging underestimates inflow velocities, and overestimates the mitral annular velocity, velocity ratios are consistently correlated with Doppler echocardiography

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC. Brunton et al. demonstrate that differential chromatin accessibility can predict responsiveness and tolerance to GSK3β inhibitors in the squamous subtype of PDAC. This study provides an important proof of concept that chromatin accessibility can be used to identify additional PDAC subgroups with potential therapeutic utility.</p