Background: The development of clinically applicable fluid-structure interaction (FSI) models of the left heart is inherently challenging when using in vivo cardiovascular magnetic resonance (CMR) data for validation, due to the lack of a well-controlled system where detailed measurements of the ventricular wall motion and flow field are available a priori. The purpose of this study was to (a) develop a clinically relevant, CMR-compatible left heart physical model; and (b) compare the left ventricular (LV) volume reconstructions and hemodynamic data obtained using CMR to laboratory-based experimental modalities. Methods: The LV was constructed from optically clear flexible silicone rubber. The geometry was based off a healthy patient's LV geometry during peak systole. The LV phantom was attached to a left heart simulator consisting of an aorta, atrium, and systemic resistance and compliance elements. Experiments were conducted for heart rate of 70 bpm. Wall motion measurements were obtained using high speed stereo-photogrammetry (SP) and cine-CMR, while flow field measurements were obtained using digital particle image velocimetry (DPIV) and phase-contrast magnetic resonance (PC-CMR). Results: The model reproduced physiologically accurate hemodynamics (aortic pressure = 120/80 mmHg; cardiac output = 3.5 L/min). DPIV and PC-CMR results of the center plane flow within the ventricle matched, both qualitatively and quantitatively, with flow from the atrium into the LV having a velocity of about 1.15 m/s for both modalities. The normalized LV volume through the cardiac cycle computed from CMR data matched closely to that from SP. The mean difference between CMR and SP was 5.5 ± 3.7 %. Conclusions: The model presented here can thus be used for the purposes of: (a) acquiring CMR data for validation of FSI simulations, (b) determining accuracy of cine-CMR reconstruction methods, and (c) conducting investigations of the effects of altering anatomical variables on LV function under normal and disease conditions.
Background: Using a bifurcated Y-graft as the Fontan baffle is hypothesized to streamline and improve flow dynamics through the total cavopulmonary connection (TCPC). This study conducted numerical simulations to evaluate this hypothesis using postoperative data from 5 patients. Methods: Patients were imaged with cardiac magnetic resonance or computed tomography after receiving a bifurcated aorto-iliac Y-graft as their Fontan conduit. Numerical simulations were performed using in vivo flow rates, as well as 2 levels of simulated exercise. Two TCPC models were virtually created for each patient to serve as the basis for hemodynamic comparison. Comparative metrics included connection flow resistance and inferior vena caval flow distribution. Results: Results demonstrate good hemodynamic outcomes for the Y-graft options. The consistency of inferior vena caval flow distribution was improved over TCPC controls, whereas the connection resistances were generally no different from the TCPC values, except for 1 case in which there was a marked improvement under both resting and exercise conditions. Examination of the connection hemodynamics as they relate to surgical Y-graft implementation identified critical strategies and modifications that are needed to potentially realize the theoretical efficiency of such bifurcated connection designs. Conclusions: Five consecutive patients received a Y-graft connection to complete their Fontan procedure with positive hemodynamic results. Refining the surgical technique for implementation should result in further energetic improvements that may help improve long-term outcomes.
The Fontan procedure, although an imperfect solution for children born with a single functional ventricle, is the only reconstruction at present short of transplantation. The haemodynamics associated with the total cavopulmonary connection, the modern approach to Fontan, are severely altered from the normal biventricular circulation and may contribute to the long-term complications that are frequently noted. Through recent technological advances, spear-headed by advances in medical imaging, it is now possible to virtually model these surgical procedures and evaluate the patient-specific haemodynamics as part of the pre-operative planning process. This is a novel paradigm with the potential to revolutionise the approach to Fontan surgery, help to optimise the haemodynamic results, and improve patient outcomes. This review provides a brief overview of these methods, presents preliminary results of their clinical usage, and offers insights into its potential future directions.
Postoperative suture dehiscence is an important mode of short-term mitral and tricuspid valve (MV, TV) repair failure. We sought to evaluate suture pullout forces and collagen density in human atrioventricular valves for a better understanding of the comparative physiology between the valves and the underlying mechanobiological basis for suture retention. Mitral and tricuspid annuli were each excised from hearts from human donors age 60–79 with no history of heart disease (n = 6). Anchor sutures were vertically pulled until tearing through the tissue. Suture pullout force (FP) was measured as the maximum force at dehiscence.
Subsequently, tissue samples from each tested suture position were evaluated for collagen content using a standard hydroxyproline assay. Among all mitral positions, no significant differences were detected among positions or regions with mean FP values falling between 6.9 ± 2.6 N (posterior region) and 10.3 ± 4.7 N (anterior region). Among all tricuspid positions, the maximum FP and minimum FP were 24.0 ± 9.2 N (trigonal region) and 4.5 ± 2.6 N (anterior region). Although for the MV, a given sample’s collagen content had no correlation to its corresponding FP, the same relationship was significant for the TV. Further, the TV exhibited comparable FP to the MV overall, despite a nearly 40% reduction in collagen content.
These findings suggest that sutures placed in the trigonal region of the TV have higher pullout force than those placed along other segments of the annuli. Furthermore, there are likely differences in collagen orientation between the mitral and tricuspid annuli, such that collagen content strongly impacts FP in one, but not the other.
Objective - Calcific aortic valve (AV) disease, characterized by AV sclerosis and calcification, is a major cause of death in the aging population; however, there are no effective medical therapies other than valve replacement. AV calcification preferentially occurs on the fibrosa side, exposed to disturbed flow (d-flow), whereas the ventricularis side exposed to predominantly stable flow remains protected by unclear mechanisms. Here, we tested the role of novel flow-sensitive UBE2C (ubiquitin E2 ligase C) and microRNA-483-3p (miR-483) in flow-dependent AV endothelial function and AV calcification.
Approach and Results - Human AV endothelial cells and fresh porcine AV leaflets were exposed to stable flow or d-flow. We found that UBE2C was upregulated by d-flow in human AV endothelial cells in the miR-483-dependent manner. UBE2C mediated OS-induced endothelial inflammation and endothelial-mesenchymal transition by increasing the HIF-1α (hypoxia-inducible factor-1α) level. UBE2C increased HIF-1α by ubiquitinating and degrading its upstream regulator pVHL (von Hippel-Lindau protein). These in vitro findings were corroborated by immunostaining studies using diseased human AV leaflets. In addition, we found that reduction of miR-483 by d-flow led to increased UBE2C expression in human AV endothelial cells. The miR-483 mimic protected against endothelial inflammation and endothelial-mesenchymal transition in human AV endothelial cells and calcification of porcine AV leaflets by downregulating UBE2C. Moreover, treatment with the HIF-1α inhibitor (PX478) significantly reduced porcine AV calcification in static and d-flow conditions.
Conclusions - These results suggest that miR-483 and UBE2C and pVHL are novel flow-sensitive anti- and pro-calcific AV disease molecules, respectively, that regulate the HIF-1α pathway in AV. The miR-483 mimic and HIF-1α pathway inhibitors may serve as potential therapeutics of calcific AV disease.
Computational models of the heart's mitral valve (MV) exhibit potential for preoperative surgical planning in ischemic mitral regurgitation (IMR). However challenges exist in defining boundary conditions to accurately model the function and response of the chordae tendineae to both IMR and surgical annuloplasty repair. Towards this goal, a ground-truth data set was generated by quantifying the isolated effects of IMR and mitral annuloplasty on leaflet coaptation, regurgitation, and tethering forces of the anterior strut and posterior intermediary chordae tendineae. MVs were excised from ovine hearts (N = 15) and mounted in a pulsatile heart simulator which has been demonstrated to mimic the systolic MV geometry and coaptation of healthy and chronic IMR sheep. Strut and intermediary chordae from both MV leaflets (N = 4) were instrumented with force transducers. Tested conditions included a healthy control, IMR, oversized annuloplasty, true-sized annuloplasty, and undersized mitral annuloplasty. A2-P2 leaflet coaptation length, regurgitation, and chordal tethering were quantified and statistically compared across experimental conditions. MR was successfully simulated with significant increases in MR, tethering forces for each of the chordae, and decrease in leaflet coaptation (p < .05). Compared to the IMR condition, increasing levels of downsized annuloplasty significantly reduced regurgitation, increased coaptation, reduced posteromedial papillary muscle strut chordal forces, and reduced intermediary chordal forces from the anterolateral papillary muscle (p < .05). These results provide for the first time a novel comprehensive data set for refining the ability of computational MV models to simulate IMR and varying sizes of complete rigid ring annuloplasty.
by
Andrew W. Siefert;
Jean Pierre Rabbah;
Kevin J. Koomalsingh;
Steven A. Touchton;
Neelakantan Saikrishnan;
Jeremy R. McGarvey;
Robert C. Gorman;
Joseph H. Gorman, lll;
Ajit Yoganathan
Background: This study was undertaken to evaluate an in vitro mitral valve (MV) simulator's ability to mimic the systolic leaflet coaptation, regurgitation, and leaflet mechanics of a healthy ovine model and an ovine model with chronic ischemic mitral regurgitation (IMR).
Methods: Mitral valve size and geometry of both healthy ovine animals and those with chronic IMR were used to recreate systolic MV function in vitro. A2-P2 coaptation length, coaptation depth, tenting area, anterior leaflet strain, and MR were compared between the animal groups and valves simulated in the bench-top model.
Results: For the control conditions, no differences were observed between the healthy animals and simulator in coaptation length (p = 0.681), coaptation depth (p = 0.559), tenting area (p = 0.199), and anterior leaflet strain in the radial (p = 0.230) and circumferential (p = 0.364) directions. For the chronic IMR conditions, no differences were observed between the models in coaptation length (p = 0.596), coaptation depth (p = 0.621), tenting area (p = 0.879), and anterior leaflet strain in the radial (p = 0.151) and circumferential (p = 0.586) directions. MR was similar between IMR models, with an asymmetrical jet originating from the tethered A3-P3 leaflets.
Conclusions: This study is the first to demonstrate the effectiveness of an in vitro simulator to emulate the systolic valvular function and mechanics of a healthy ovine model and one with chronic IMR. The in vitro IMR model provides the capability to recreate intermediary and exacerbated levels of annular and subvalvular distortion for which IMR repairs can be simulated. This system provides a realistic and controllable test platform for the development and evaluation of current and future IMR repairs.
by
Charles H. Bloodworth;
Eric L. Pierce;
Keshav Kohli;
Nancy J. Deaton;
Kaitlin J. Jones;
Radhika Duvvuri;
Norihiko Kamioka;
Vasilis Babaliaros;
Ajit Yoganathan
Objectives: We aimed to evaluate diastolic leaflet tethering as a factor that may cause mitral stenosis (MS) after simulated MitraClip implantation, using an in vitro left heart simulator.
Background: Leaflet tethering commonly seen in functional mitral regurgitation may be a significant factor affecting the severity of MS after MitraClip implantation.
Methods: A left heart simulator with excised ovine mitral valves (N = 6), and custom edge-to-edge clip devices (GTclip) was used to mimic implantation of MitraClip in a variety of positions. Anterior mitral leaflet (AML) tethering severity was varied for each case (leaflet excursion of 75°, 60°, and 45°, consistent with mild, moderate and severe tethering), and the baseline mitral annular area (MAA) was varied across samples (3.6–4.8 cm2). The resulting mitral valve area (MVA), and peak/mean mitral valve gradient (MVG) were measured in each case.
Results: AML tethering severity was a highly significant factor increasing MVG and decreasing MVA (P < 0.001). When GTclip placement was simulated with severe AML tethering, mean MVG >5 mmHg resulted more frequently than with GTclip placement alone (46% vs. 4%, respectively). However, severe AML tethering alone significantly reduced baseline MVA to 3.6 ± 0.2 cm2, and increased baseline MVG to 3.0 ± 0.4 mmHg. At MAA above 4.7 cm2, severe AML tethering did not cause moderate MS, even with placement of two GTclips (95% confidence).
Conclusions: Our results show that diastolic AML tethering may predispose to MS after clip placement, however, MS was not observed when baseline MVA was above 4.0 cm2. Severity of AML tethering may be an important criterion in selecting patients for edge-to-edge repair.
Limited knowledge exists regarding the forces which act on devices implanted to the heart's mitral valve. Developing a transducer to measure the peak force magnitudes, time rates of change, and relationship with left ventricular pressure will aid in device development. A novel force transducer was developed and implanted in the mitral valve annulus of an ovine subject. In the post-cardioplegic heart, septal-lateral and transverse forces were continuously measured for cardiac cycles reaching a peak left ventricular pressure of 90. mmHg. Each force was seen to increase from ventricular diastole and found to peak at mid-systole. The mean change in septal-lateral and transverse forces throughout the cardiac cycle was 4.4±0.2. N and 1.9±0.1. N respectively. During isovolumetric contraction, the septal-lateral and transverse forces were found to increase at peak rate of 143±8. N/s and 34±9. N/s, respectively. Combined, this study provides the first quantitative assessment of septal-lateral and transverse forces within the contractile mitral annulus. The developed transducer was successful in measuring these forces whose methods may be extended to future studies. Upon additional investigation, these data may contribute to the safer development and evaluation of devices aimed to repair or replace mitral valve function.
by
Andrew W. Siefert;
Steven A. Touchton;
Jeremy R. McGarvey;
Satoshi Takebayashi;
Jean Pierre M. Rabbah;
Jorge H. Jimenez;
Neelakantan Saikrishnan;
Robert C. Gorman;
Joseph H. Gorman, lll;
Ajit Yoganathan
Mitral annuloplasty has been a keystone to the success of mitral valve repair in functional mitral regurgitation. Understanding the complex interplay between annular-ring stresses and left ventricular function has significant implications for patient-ring selection, repair failure, and patient safety. A step towards assessing these challenges is developing a transducer that can be implanted in the exact method as commercially available rings and can quantify multidirectional ring loading. An annuloplasty ring transducer was developed to measure stresses at eight locations on both the in-plane and out-of-plane surfaces of an annuloplasty ring's titanium core. The transducer was implanted in an ovine subject using 10 sutures at near symmetric locations. At implantation, the ring was observed to undersize the mitral annulus. The flaccid annulus exerted both compressive (-) and tensile stresses (+) on the ring ranging from -3.17 to 5.34. MPa. At baseline hemodynamics, stresses cyclically changed and peaked near mid-systole. Mean changes in cyclic stress from ventricular diastole to mid-systole ranged from -0.61 to 0.46. MPa (in-plane direction) and from -0.49 to 1.13. MPa (out-of-plane direction). Results demonstrate the variability in ring stresses that can be introduced during implantation and the cyclic contraction of the mitral annulus. Ring stresses at implantation were approximately 4 magnitudes larger than the cyclic changes in stress throughout the cardiac cycle. These methods will be extended to ring transducers of differing size and geometry. Upon additional investigation, these data will contribute to improved knowledge of annulus-ring stresses, LV function, and the safer development of mitral repair techniques.