Person:

Del Nido, Pedro

Segmenting the mitral valve during closure and throughout a cardiac cycle from four dimensional ultrasound (4DUS) is important for creation and validation of mechanical models and for improved visualization and understanding of mitral valve behavior. Current methods of segmenting the valve from 4DUS either require extensive user interaction and initialization, do not maintain the valve geometry across a cardiac cycle, or are incapable of producing a detailed coaptation line and surface. We present a method of segmenting the mitral valve annulus and leaflets from 4DUS such that a detailed, patient-specific annulus and leaflets are tracked throughout mitral valve closure, resulting in a detailed coaptation region. The method requires only the selection of two frames from a sequence indicating the start and end of valve closure and a single point near a closed valve. The annulus and leaflets are first found through direct segmentation in the appropriate frames and then by tracking the known geometry to the remaining frames. We compared the automatically segmented meshes to expert manual tracings for both a normal and diseased mitral valve, and found an average difference of 0.59 ± 0.49mm, which is on the order of the spatial resolution of the ultrasound volumes (0.5–1.0mm/voxel).

Background: Cyanosis and myocardial hypertrophy frequently occur in combination. Hypoxia or cyanosis can be potent inducers of angiogenesis, regulating the expression of hypoxia-inducible factors (HIF), vascular endothelial growth factors (VEGF), and VEGF receptors (VEGFR-1 and 2); in contrast, pressure overload hypertrophy is often associated with impaired pro-angiogenic signaling and decreased myocardial capillary density. We hypothesized that the physiological pro-angiogenic response to cyanosis in the hypertrophied myocardium is blunted through differential HIF and VEGF-associated signaling. Methods and Results: Newborn rabbits underwent aortic banding and, together with sham-operated littermates, were transferred into a hypoxic chamber (FiO2 = 0.12) at 3 weeks of age. Control banded or sham-operated rabbits were housed in normoxia. Systemic cyanosis was confirmed (hematocrit, arterial oxygen saturation, and serum erythropoietin). Myocardial tissue was assayed for low oxygen concentrations using a pimonidazole adduct. At 4 weeks of age, HIF-1α and HIF-2α protein levels, HIF-1α DNA-binding activity, and expression of VEGFR-1, VEGFR-2, and VEGF were determined in hypoxic and normoxic rabbits. At 6 weeks of age, left-ventricular capillary density was assessed by immunohistochemistry. Under normoxia, capillary density was decreased in the banded rabbits compared to non-banded littermates. As expected, non-hypertrophied hearts responded to hypoxia with increased capillary density; however, banded hypoxic rabbits demonstrated no increase in angiogenesis. This blunted pro-angiogenic response to hypoxia in the hypertrophied myocardium was associated with lower HIF-2α and VEGFR-2 levels and increased HIF-1α activity and VEGFR-1 expression. In contrast, non-hypertrophied hearts responded to hypoxia with increased HIF-2α and VEGFR-2 expression with lower VEGFR-1 expression. Conclusion: The participation of HIF-2α and VEGFR-2 appear to be required for hypoxia-stimulated myocardial angiogenesis. In infant rabbit hearts with pressure overload hypertrophy, this pro-angiogenic response to hypoxia is effectively uncoupled, apparently in part due to altered HIF-mediated signaling and VEGFR subtype expression.

Heart valves are functionally complex, making surgical repair difficult. Simulation-based surgical planning could facilitate repair, but current finite element studies are prohibitively slow for rapid, clinically-oriented simulations. An anisotropic, nonlinear mass-spring (M-S) model is used to approximate the behavior of valve leaflets and applied to fully image-based mitral valve models to simulate valve closure for fast applications like intraoperative surgical planning. This approach is used to simulate a technique used in valve repair and to assess the role of chordae in determining the closed configuration of the valve. Direct image-based comparison is used for validation. Results of M-S model simulations showed that it is possible to build fully image-based models of the mitral valve and to rapidly simulate closure with sub-millimeter accuracy. Chordae, which are presently difficult to image, are shown to be strong determinants of closed valve shape.

Heart valves are functionally complex, making surgical repair difficult. Simulation-based surgical planning could facilitate repair, but current finite element (FE) studies are prohibitively slow for rapid, clinically oriented simulations. Mass-spring (M-S) models are fast but can be inaccurate. We quantify speed and accuracy differences between an anisotropic, nonlinear M-S and an efficient FE membrane model for simulating both biaxial and pressure loading of aortic valve (AV) leaflets. The FE model incurs approximately 10 times the computational cost of the M-S model. For simulated biaxial loading, mean error in normal strains is <1% for both FE and M-S models for equibiaxial loading but increases for non-equibiaxial states for the M-S model (7%). The M-S model was less able to simulate shear behavior, with mean strain error of approximately 80%. For pressurized AV leaflets, the M-S model predicts similar leaflet dimensions to the FE model (within 2.6%), and the coaptation zone is similar between models. The M-S model simulates in-plane behavior of AV leaflets considerably faster than the FE model and with only minor differences in the deformed mesh. While the M-S model does not allow explicit control of shear response, shear does not strongly influence shape of the simulated AV under pressure.

Background. Endocardial fibroelastosis (EFE), characterized by a diffuse endocardial thickening through collagen and elastin fibers, develops in the human fetal heart restricting growth of the left ventricle (LV). Recent advances in fetal imaging indicate that EFE development is directly associated with a distended, poorly contractile LV in evolving hypoplastic left heart syndrome (HLHS). In this study, we developed an animal model of EFE by introducing this human fetal LV morphopathology to an immature rat heart. Methods and Results. A neonatal donor heart, in which aortic regurgitation (AR) was created, was heterotopically transplanted into a recipient adult rat. AR successfully induced the LV morphology of evolving HLHS in the transplanted donor hearts, which resulted in the development of significant EFE covering the entire LV cavity within two weeks postoperatively. In contrast, posttransplants with a competent aortic valve displayed unloaded LVs with a trace of EFE. Conclusions. We could show that distention of the immature LV in combination with stagnant flow triggers EFE development in this animal model. This model would serve as a robust tool to develop therapeutic strategies to treat EFE while providing insight into its pathogenesis.

Previously, we have demonstrated that the transplantation of viable, structurally intact, respiration competent mitochondria into the ischemic myocardium during early reperfusion significantly enhanced cardioprotection by decreasing myocellular damage and enhancing functional recovery. Our in vitro and in vivo studies established that autologous mitochondria are internalized into cardiomyocytes following transplantation; however, the mechanism(s) modulating internalization of these organelles were unknown. Here, we show that internalization of mitochondria occurs through actin-dependent endocytosis and rescues cell function by increasing ATP content and oxygen consumption rates. We also show that internalized mitochondria replace depleted mitochondrial (mt)DNA. These results describe the mechanism for internalization of mitochondria within host cells and provide a basis for novel therapeutic interventions allowing for the rescue and replacement of damaged or impaired mitochondria.

Background: Accurate calculation of ventricular stress and strain is critical for cardiovascular investigations. Sarcomere shortening in active contraction leads to change of ventricular zero-stress configurations during the cardiac cycle. A new model using different zero-load diastole and systole geometries was introduced to provide more accurate cardiac stress/strain calculations with potential to predict post pulmonary valve replacement (PVR) surgical outcome. Methods: Cardiac magnetic resonance (CMR) data were obtained from 16 patients with repaired tetralogy of Fallot prior to and 6 months after pulmonary valve replacement (8 male, 8 female, mean age 34.5 years). Patients were divided into Group 1 (n = 8) with better post PVR outcome and Group 2 (n = 8) with worse post PVR outcome based on their change in RV ejection fraction (EF). CMR-based patient-specific computational RV/LV models using one zero-load geometry (1G model) and two zero-load geometries (diastole and systole, 2G model) were constructed and RV wall thickness, volume, circumferential and longitudinal curvatures, mechanical stress and strain were obtained for analysis. Pairwise T-test and Linear Mixed Effect (LME) model were used to determine if the differences from the 1G and 2G models were statistically significant, with the dependence of the pair-wise observations and the patient-slice clustering effects being taken into consideration. For group comparisons, continuous variables (RV volumes, WT, C- and L- curvatures, and stress and strain values) were summarized as mean ± SD and compared between the outcome groups by using an unpaired Student t-test. Logistic regression analysis was used to identify potential morphological and mechanical predictors for post PVR surgical outcome. Results: Based on results from the 16 patients, mean begin-ejection stress and strain from the 2G model were 28% and 40% higher than that from the 1G model, respectively. Using the 2G model results, RV EF changes correlated negatively with stress (r = -0.609, P = 0.012) and with pre-PVR RV end-diastole volume (r = -0.60, P = 0.015), but did not correlate with WT, C-curvature, L-curvature, or strain. At begin-ejection, mean RV stress of Group 2 was 57.4% higher than that of Group 1 (130.1±60.7 vs. 82.7±38.8 kPa, P = 0.0042). Stress was the only parameter that showed significant differences between the two groups. The combination of circumferential curvature, RV volume and the difference between begin-ejection stress and end-ejection stress was the best predictor for post PVR outcome with an area under the ROC curve of 0.855. The begin-ejection stress was the best single predictor among the 8 individual parameters with an area under the ROC curve of 0.782. Conclusion: The new 2G model may be able to provide more accurate ventricular stress and strain calculations for potential clinical applications. Combining morphological and mechanical parameters may provide better predictions for post PVR outcome.

Beating heart intracardiac procedures promise significant benefits for patients, however, the fast motion of the heart poses serious challenges to surgeons. We present a new 3D ultrasound-guided motion (3DUS) compensation system that synchronizes instrument motion with the heart. The system utilizes the fact that the motion of some intracardiac structures, including the mitral valve annulus, is largely constrained to translation along one axis. This allows the development of a real-time 3DUS tissue tracker which we integrate with a 1 degree-of-freedom actuated surgical instrument, real-time 3DUS instrument tracker, and predictive filter to devise a system with synchronization accuracy of 1.8 mm RMSE. User studies involving the deployment of surgical anchors in a simulated mitral annuloplasty procedure demonstrate that the system increases success rates by over 100%. Furthermore, it enables more careful anchor deployment by reducing forces to the tissue by 50% while allowing instruments to remain in contact with the tissue for longer periods.

The manipulation of fast moving, delicate tissues in beating heart procedures presents a considerable challenge to the surgeon. A robotic force tracking system can assist the surgeon by applying precise contact forces to the beating heart during surgical manipulation. Standard force control approaches cannot safely attain the required bandwidth for this application due to vibratory modes within the robot structure. These vibrations are a limitation even for single degree of freedom systems driving long surgical instruments. These bandwidth limitations can be overcome by incorporating feed-forward motion terms in the control law. For intracardiac procedures, the required motion estimates can be derived from 3D ultrasound imaging. Dynamic analysis shows that a force controller with feed-forward motion terms can provide safe and accurate force tracking for contact with structures within the beating heart. In vivo validation confirms that this approach confers a 50% reduction in force fluctuations when compared to a standard force controller and a 75% reduction in fluctuations when compared to manual attempts to maintain the same force.

The manipulation of fast moving, delicate tissues in beating heart procedures presents a considerable challenge to surgeons. We present a new robotic force stabilization system that assists surgeons by maintaining a constant contact force with the beating heart. The system incorporates a novel, miniature uniaxial force sensor that is mounted to surgical instrumentation to measure contact forces during surgical manipulation. Using this sensor in conjunction with real-time tissue motion information derived from 3D ultrasound, we show that a force controller with feed-forward motion terms can provide safe and accurate force stabilization in an in vivo contact task against the beating mitral valve annulus. This confers a 50% reduction in force fluctuations when compared to a standard force controller and a 75% reduction in fluctuations when compared to manual attempts to maintain the same force.