Christopher J. Occleshaw

Regeneration of the Heart in Diabetes by Selective Copper Chelation

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.

Age-Related Changes in Myocardial Relaxation Using Three-Dimensional Tagged Magnetic Resonance Imaging

PURPOSE Marked changes in left ventricular diastolic filling occur with advancing age, but alterations in myocardial movement accompanying these findings have not been previously documented. We aimed to identify differences in myocardial motion during relaxation and diastole using magnetic resonance imaging (MRI), with tagging, which uniquely allows accurate, noninvasive assessment of myocardial movement in three dimensions. METHODS Tagged MRI images from two groups of normal individuals were analyzed using dedicated computer software to provide values for group comparison of apical rotation, torsion, and circumferential and longitudinal strain throughout the cardiac cycle. RESULTS The mean age of the younger group was 22 years, (n = 15) and that of the older group was 69 years, (n = 16). In the older group, peak apical rotation and torsion were increased during systole and significantly more apical rotation, torsion, circumferential, and longitudinal strain persisted during myocardial relaxation and diastole. In addition, peak normalized reversal of apical rotation was reduced (-5.1 +/- 1.2 degrees s-1 vs. -6.7 +/- 1.2 degrees s-1, p = 0.001), and there were slower peak rates of circumferential lengthening (76.2 +/- 28% s-1 vs. 142.5 +/- 17% s-1, p < 0.001) and longitudinal lengthening (62.7 +/- 21% s-1 vs. 122.5 +/- 20% s-1, p < 0.001). CONCLUSIONS Tagged MRI is a unique, noninvasive imaging method that can identify significant prolongation and reduction of myocardial relaxation in older compared with young normal individuals.

Temporal Evolution of Left Ventricular Strain Late After Repair of Coarctation of the Aorta Using 3D MR Tissue Tagging

PURPOSE Following repair of coarctation of the aorta (CoA), LV mass is increased along with morbidity and mortality. Previous studies have reported increased shortening indices and impaired diastolic function. However, direct measurements of local material motion and temporal evolution of strain have been lacking. METHODS Magnetic resonance (MR) tissue tagging was used to quantify regional three-dimensional myocardial deformation throughout systole and much of diastole in 14 patients (aged 19-23) who had CoA repair 17-23 years previously, and 15 age-, sex- and BSA-matched normal volunteers (NV). RESULTS Mass to end-diastolic volume ratio was increased in the CoA group (1.23 +/- 0.12 g/mL CoA vs. 1.14 +/- 0.10 g/mL NV, p = 0.039), together with ejection fraction (65.3 +/- 4.4 vs. 60.8 +/-1.9%, p = 0.001) and systolic blood pressure (132.5 +/- 14.5 vs. 117.3 +/- 11.6 mmHg, p = 0.004). At end-systole, circumferential shortening was normal, but longitudinal shortening was decreased (14.9 +/- 1.3 vs. 16.8 +/- 1.4%, p < 0.001). Although systolic strain rates were not significantly different, early diastolic strain rate (EDSR) in the CoA group was increased in the circumferential direction (-71 +/- 23 vs. -52 +/- 20%/sec, p = 0.029), but decreased in the longitudinal direction (-27 +/- 12 vs. -39 +/- 11%/sec, p = 0.015). Longitudinal shortening and circumferential EDSR were related to right arm-leg pressure gradient (R2 = 0.20, p = 0.016 and R2 = 0.38, p < 0.001, respectively) and to mass index (R2 = 0.18, p = 0.024 and R2 = 014, p = 0.049, respectively). CONCLUSIONS MR tagging allows quantitative information on the temporal evolution of myocardial deformation. Directionally dependent changes in strain evolution are seen late after CoA repair. These changes are related to both persistent arm-leg pressure gradient and degree of hypertrophy and may be indicators of developing dysfunction.

Wall Shear Stress is the Primary Mechanism of Energy Loss in the Fontan Connection

Long-term outcome following the Fontan operation may be affected by the amount of energy lost as blood flows through the anastomosis geometry. A method for detailed quantification of energy loss is applied to computational simulations of the flow in an atriopulmonary and a total cavopulmonary model. Five types of flow (near wall, slow recirculation, medium speed vortices, collision, and streamlined flow) are identified and their energy losses quantified. The presence of recirculation regions decreases the efficiency of the atriopulmonary model, and a region of increased energy loss is seen in the collision region in the total cavopulmonary model. However, the most significant energy loss is through wall shear stress, which is maximal in areas where there is rapid, near wall flow.

Rapid D-Affine biventricular cardiac function with polar prediction.

Although many solutions have been proposed for left ven-tricular functional analysis of the heart, right and left (bi-) ventricular function has been problematic due to the complex geometry and large motions. Biventricular function is particularly important in congenital heart disease, the most common type of birth defects. We describe a rapid interactive analysis tool for biventricular function which incorporates 1) a 3D+ time finite element model of biventricular geometry, 2) a fast prediction step which estimates an initial geometry in a polar coordinate system, and 3) a Cartesian update which penalizes deviations from affine transformations (D-Affine) from a prior. Solution times were very rapid, enabling interaction in real time using guide point modeling. The method was applied to 13 patients with congenital heart disease and compared with the clinical gold standard of manual tracing. Results between the methods showed good correlation (R2 > 0.9) and good precision (volume < 17 ml; mass < 11g) for both chambers.

An interactive tool for rapid biventricular analysis of congenital heart disease.

Cardiac malformations are the most common birth defect. Better interventions in early life have improved mortality for children with congenital heart disease, but heart failure is a significant problem in adulthood. These patients require regular imaging and analysis of biventricular (left and right ventricular) function. In this study, we describe a rapid method to analyse left and right ventricular shape and function from cardiac MRI examinations. A 4D (3D+time) finite element model template is interactively customized to the anatomy and motion of the biventricular unit. The method was validated in 17 patients and 10 ex‐vivo hearts. Interactive model updates were achieved through preconditioned conjugate gradient optimization on a multithread system, and by precomputing points predicted from a coarse mesh optimization.

Creating shape templates for patient specific biventricular modeling in congenital heart disease

Survival rates for infants with congenital heart disease (CHD) are improving, resulting in a growing population of adults with CHD. However, the analysis of left and right ventricular function is very time-consuming owing to the variety of congenital morphologies. Efficient customization of patient geometry and function depends on high quality shape templates specifically designed for the application. In this paper, we combine a method for creating finite element shape templates with an interactive template customization to patient MRI examinations. This enables different templates to be chosen depending on patient morphology. To demonstrate this pipeline, a new biventricular template with 162 elements was created and tested in place of an existing 82-element template. The method was able to provide fast interactive biventricular analysis with 0.31 sec per edit response time. The new template was customized to 13 CHD patients with similar biventricular topology, showing improved performance over the previous template and good agreement with clinical indices.

Estimation of myocardial strain from non-rigid registration and highly accelerated cine CMR

Sparsely sampled cardiac cine accelerated acquisitions show promise for faster evaluation of left-ventricular function. Myocardial strain estimation using image feature tracking methods is also becoming widespread. However, it is not known whether highly accelerated acquisitions also provide reliable feature tracking strain estimates. Twenty patients and twenty healthy volunteers were imaged with conventional 14-beat/slice cine acquisition (STD), 4× accelerated 4-beat/slice acquisition with iterative reconstruction (R4), and a 9.2× accelerated 2-beat/slice real-time acquisition with sparse sampling and iterative reconstruction (R9.2). Radial and circumferential strains were calculated using non-rigid registration in the mid-ventricle short-axis slice and inter-observer errors were evaluated. Consistency was assessed using intra-class correlation coefficients (ICC) and bias with Bland–Altman analysis. Peak circumferential strain magnitude was highly consistent between STD and R4 and R9.2 (ICC = 0.876 and 0.884, respectively). Average bias was −1.7 ± 2.0 %, p < 0.001, for R4 and −2.7 ± 1.9 %, p < 0.001 for R9.2. Peak radial strain was also highly consistent (ICC = 0.829 and 0.785, respectively), with average bias −11.2 ± 18.4 %, p < 0.001, for R4 and −15.0 ± 21.2 %, p < 0.001 for R9.2. STD circumferential strain could be predicted by linear regression from R9.2 with an R2 of 0.82 and a root mean squared error of 1.8 %. Similarly, radial strain could be predicted with an R2 of 0.67 and a root mean squared error of 21.3 %. Inter-observer errors were not significantly different between methods, except for peak circumferential strain R9.2 (1.1 ± 1.9 %) versus STD (0.3 ± 1.0 %), p = 0.011. Although small systematic differences were observed in strain, these were highly consistent with standard acquisitions, suggesting that accelerated myocardial strain is feasible and reliable in patients who require short acquisition durations.

Improving assessment of congenital heart disease through rapid patient specific modeling

Congenital heart disease is the most common birth defect, with an incidence of 75 in every 1000 births. As a result of improved interventions, 90% of people with congenital heart disease now survive to adulthood. They must undergo regular imaging to assess their biventricular (left and right ventricular) function. Analysis of the images is problematic due to the large variety of shapes and complex geometry. In this paper we extend a biventricular modeling method to improve the analysis of MR images from congenital heart disease patients. We used a subdivision surface method to create three customizable exemplars, representing common manifestations of anatomy, and incorporated these as priors into an interactive biventricular customization procedure. The CHD-specific priors were tested on 60 cases representing a variety of congenital heart diseases for which the gold standard manual contours were available. The introduction of multiple priors showed a significant decrease in analysis time while maintaining good correlation between the two methods (R2 >.82).