Functional dynamics and allosteric modulation of TRPA1.

The cation channel TRPA1 is a potentially important drug target, and characterization of TRPA1 functional dynamics might help guide structure-based drug design. Here, we present results from long-timescale molecular dynamics simulations of TRPA1 with an allosteric activator, allyl isothiocyanate (AITC), in which we observed spontaneous transitions from a closed, non-conducting channel conformation into an open, conducting conformation. Based on these transitions, we propose a gating mechanism in which movement of a regulatory TRP-like domain allosterically translates into pore opening in a manner reminiscent of pore opening in voltage-gated ion channels. In subsequent experiments, we found that mutations that disrupt packing of the S4-S5 linker-TRP-like domain and the S5 and S6 helices also affected channel activity. In simulations, we also observed A-967079, a known allosteric inhibitor, binding between helices S5 and S6, suggesting that A-967079 may suppress activity by stabilizing a non-conducting pore conformation-a finding consistent with our proposed gating mechanism.

Design, fabrication, and evaluation of 3-D-printed cystotomy spoons as a retrieval method in dogs.

OBJECTIVE: Current cystotomy methods often implement the use of off-label devices, resulting in urocystolith extraction difficulty and potentially leading to postoperative complications and discomfort for the patient. The objective of this study was to create 3 novel 3-D printed cystotomy spoons that offer a dedicated solution for removing urocystoliths from a patient's urinary bladder. ANIMALS: Clinical use of the 3 novel 3-D printed cystotomy spoons were ultimately evaluated in 4 dogs and 1 cat that presented for urocystotlith removal at 3 different veterinary hospitals in northwest Arkansas. METHODS: The novel cystotomy spoons were designed using SolidWorks, 3-D printed with a Dental Surgical Guide resin, and underwent prototype testing that included chlorhexidine soaking, autoclave sterilization, 3-point bend testing, and Finite Element Analysis. The efficiency of the spoons was then evaluated through a limited proof-of-concept study utilizing a postoperative questionnaire for the participating clinicians. RESULTS: Practitioner feedback indicated positive experiences using 1 or more of the novel 3-D printed cystotomy spoons while performing a cystotomy surgery. However, successful use of the spoons was ultimately limited to dogs in the 23 to 34 kg weight range. CLINICAL RELEVANCE: Novel 3-D printed cystotomy spoons have the potential to mediate urocystolith extraction difficulty and reduce postoperative complications. Additionally, this research demonstrates how veterinarians might develop custom 3-D models and prints to meet patient-specific needs. As such, further development could impact the standard of healthcare and the veterinary industry by promoting the use of additive manufacturing in veterinary medicine.

Utilization of Engineering Advances for Detailed Biomechanical Characterization of the Mitral-Ventricular Relationship to Optimize Repair Strategies: A Comprehensive Review.

The geometrical details and biomechanical relationships of the mitral valve-left ventricular apparatus are very complex and have posed as an area of research interest for decades. These characteristics play a major role in identifying and perfecting the optimal approaches to treat diseases of this system when the restoration of biomechanical and mechano-biological conditions becomes the main target. Over the years, engineering approaches have helped to revolutionize the field in this regard. Furthermore, advanced modelling modalities have contributed greatly to the development of novel devices and less invasive strategies. This article provides an overview and narrative of the evolution of mitral valve therapy with special focus on two diseases frequently encountered by cardiac surgeons and interventional cardiologists: ischemic and degenerative mitral regurgitation.

Desensitization dynamics of the AMPA receptor.

To perform their physiological functions, amino methyl propionic acid receptors (AMPARs) cycle through active, resting, and desensitized states, and dysfunction in AMPAR activity is associated with various neurological disorders. Transitions among AMPAR functional states, however, are largely uncharacterized at atomic resolution and are difficult to examine experimentally. Here, we report long-timescale molecular dynamics simulations of dimerized AMPAR ligand-binding domains (LBDs), whose conformational changes are tightly coupled to changes in AMPAR functional states, in which we observed LBD dimer activation and deactivation upon ligand binding and unbinding at atomic resolution. Importantly, we observed the ligand-bound LBD dimer transition from the active conformation to several other conformations, which may correspond with distinct desensitized conformations. We also identified a linker region whose structural rearrangements heavily affected the transitions to and among these putative desensitized conformations, and confirmed, using electrophysiology experiments, the importance of the linker region in these functional transitions.

Gating and modulation of an inward-rectifier potassium channel.

Inward-rectifier potassium channels (Kirs) are lipid-gated ion channels that differ from other K+ channels in that they allow K+ ions to flow more easily into, rather than out of, the cell. Inward rectification is known to result from endogenous magnesium ions or polyamines (e.g., spermine) binding to Kirs, resulting in a block of outward potassium currents, but questions remain regarding the structural and dynamic basis of the rectification process and lipid-dependent channel activation. Here, we present the results of long-timescale molecular dynamics simulations starting from a crystal structure of phosphatidylinositol 4,5-bisphosphate (PIP2)-bound chicken Kir2.2 with a non-conducting pore. After introducing a mutation (G178R) that is known to increase the open probability of a homologous channel, we were able to observe transitions to a stably open, ion-conducting pore, during which key conformational changes occurred in the main activation gate and the cytoplasmic domain. PIP2 binding appeared to increase stability of the pore in its open and conducting state, as PIP2 removal resulted in pore closure, with a median closure time about half of that with PIP2 present. To investigate structural details of inward rectification, we simulated spermine binding to and unbinding from the open pore conformation at positive and negative voltages, respectively, and identified a spermine-binding site located near a previously hypothesized site between the pore cavity and the selectivity filter. We also studied the effects of long-range electrostatics on conduction and spermine binding by mutating charged residues in the cytoplasmic domain and found that a finely tuned charge density, arising from basic and acidic residues within the cytoplasmic domain, modulated conduction and rectification.

In Vitro Blood Clot Formation and Dissolution for Testing New Stroke-Treatment Devices.

Strokes are among the leading causes of death worldwide. Ischemic stroke, due to plaque or other buildup blocking blood flow to the brain, is the most common type. Although ischemic stroke is treatable, current methods have severe shortcomings with high mortality rates. Clot retrieval devices, for example, can result in physically damaged vessels and death. This study aims to create blood clots that are representative of those found in vivo and demonstrate a new method of removing them. Static blood clots were formed using a 9:1 ratio of whole sheep blood and 2.45% calcium chloride solution. This mixture was heated in a water bath at 37 °C for approximately one hour until solidified. Following clot solidification, human plasmin was introduced by various methods, including soaking, injection, and membrane perfusion, and the resulting dissolution percentages were determined. Different clot types, representative of the wide range found physiologically, were also manufactured and their dissolution characteristics evaluated. A method to reproducibly create blood clots, characteristic of those found in vivo, is essential for the production of stroke retrieval devices that can efficiently and effectively remove clots from patients with low mortality rates and little/no damage to the surrounding vessels.

Critical Information from High Fidelity Arterial and Venous Pressure Waveforms During Anesthesia and Hemorrhage.

PURPOSE: Peripheral venous pressure (PVP) waveform analysis is a novel, minimally invasive, and inexpensive method of measuring intravascular volume changes. A porcine cohort was studied to determine how venous and arterial pressure waveforms change due to inhaled and infused anesthetics and acute hemorrhage. METHODS: Venous and arterial pressure waveforms were continuously collected, while each pig was under general anesthesia, by inserting Millar catheters into a neighboring peripheral artery and vein. The anesthetic was varied from inhaled to infused, then the pig underwent a controlled hemorrhage. Pearson correlation coefficients between the power of the venous and arterial pressure waveforms at each pig's heart rate frequency were calculated for each variation in the anesthetic, as well as before and after hemorrhage. An analysis of variance (ANOVA) test was computed to determine the significance in changes of the venous pressure waveform means caused by each variation. RESULTS: The Pearson correlation coefficients between venous and arterial waveforms decreased as anesthetic dosage increased. In an opposing fashion, the correlation coefficients increased as hemorrhage occurred. CONCLUSION: Anesthetics and hemorrhage alter venous pressure waveforms in distinctly different ways, making it critical for researchers and clinicians to consider these confounding variables when utilizing pressure waveforms. Further work needs to be done to determine how best to integrate PVP waveforms into clinical decision-making.

Customizable Angioplasty Balloon-Forming Machine: Towards Precision Medicine in Coronary Bifurcation Lesion Interventions.

The ability to customize the size and shape of angioplasty balloons may be useful in many clinical and research applications of coronary and endovascular intervention. Fully customizable balloons are outside the reach of most researchers due to their prohibitive cost. A small-scale balloon-forming machine was developed to produce fully customizable balloons. This study describes the creation of this customizable balloon-forming machine and identifies the key components of manufacturing a patient-specific balloon. Using a standard balloon-shaped mold created with a novel application of 3D stereolithography-printed resin, 104 PET balloon formation tests were conducted. A statistical study was conducted in which molding temperature and inflation air pressure were independent variables ranging from 100 to 130 °C and from 3.7 to 6.8 atm, respectively. The criteria for balloon-forming success were defined; pressure and temperature combined were found to have a significant impact on the success (p = 0.011), with 120 °C and 4.76 atm resulting in the highest chance for success based on a regression model.

In Vitro Mitral Valve Model with Unrestricted Ventricular Access: Using Vacuum to Close the Valve and Enable Static Trans-Mitral Pressure.

Current in vitro models of the left heart establish the pressure difference required to close the mitral valve by sealing and pressurizing the ventricular side of the valve, limiting important access to the subvalvular apparatus. This paper describes and evaluates a system that establishes physiological pressure differences across the valve using vacuum on the atrial side. The subvalvular apparatus is open to atmospheric pressure and accessible by tools and sensors, establishing a novel technique for experimentation on atrioventricular valves. Porcine mitral valves were excised and closed by vacuum within the atrial chamber. Images were used to document and analyze closure of the leaflets. Papillary muscle force and regurgitant flow rate were measured to be 4.07 N at 120 mmHg and approximately 12.1 ml/s respectively, both of which are within clinically relevant ranges. The relative ease of these measurements demonstrates the usefulness of improved ventricular access at peak pressure/force closure.

Development of Custom Wall-Less Cardiovascular Flow Phantoms with Tissue-Mimicking Gel.

PURPOSE: Flow phantoms are used in experimental settings to aid in the simulation of blood flow. Custom geometries are available, but current phantom materials present issues with degradability and/or mimicking the mechanical properties of human tissue. In this study, a method of fabricating custom wall-less flow phantoms from a tissue-mimicking gel using 3D printed inserts is developed. METHODS: A 3D blood vessel geometry example of a bifurcated artery model was 3D printed in polyvinyl alcohol, embedded in tissue-mimicking gel, and subsequently dissolved to create a phantom. Uniaxial compression testing was performed to determine the Young's moduli of the five gel types. Angle-independent, ultrasound-based imaging modalities, Vector Flow Imaging (VFI) and Blood Speckle Imaging (BSI), were utilized for flow visualization of a straight channel phantom. RESULTS: A wall-less phantom of the bifurcated artery was fabricated with minimal bubbles and continuous flow demonstrated. Additionally, flow was visualized through a straight channel phantom by VFI and BSI. The available gel types are suitable for mimicking a variety of tissue types, including cardiac tissue and blood vessels. CONCLUSION: Custom, tissue-mimicking flow phantoms can be fabricated using the developed methodology and have potential for use in a variety of applications, including ultrasound-based imaging methods. This is the first reported use of BSI with an in vitro flow phantom.

Anesthetics affect peripheral venous pressure waveforms and the cross-talk with arterial pressure.

Analysis of peripheral venous pressure (PVP) waveforms is a novel method of monitoring intravascular volume. Two pediatric cohorts were studied to test the effect of anesthetic agents on the PVP waveform and cross-talk between peripheral veins and arteries: (1) dehydration setting in a pyloromyotomy using the infused anesthetic propofol and (2) hemorrhage setting during elective surgery for craniosynostosis with the inhaled anesthetic isoflurane. PVP waveforms were collected from 39 patients that received propofol and 9 that received isoflurane. A multiple analysis of variance test determined if anesthetics influence the PVP waveform. A prediction system was built using k-nearest neighbor (k-NN) to distinguish between: (1) PVP waveforms with and without propofol and (2) different minimum alveolar concentration (MAC) groups of isoflurane. 52 porcine, 5 propofol, and 7 isoflurane subjects were used to determine the cross-talk between veins and arteries at the heart and respiratory rate frequency during: (a) during and after bleeding with constant anesthesia, (b) before and after propofol, and (c) at each MAC value. PVP waveforms are influenced by anesthetics, determined by MANOVA: p value < 0.01, η2 = 0.478 for hypovolemic, and η2 = 0.388 for euvolemic conditions. The k-NN prediction models had 82% and 77% accuracy for detecting propofol and MAC, respectively. The cross-talk relationship at each stage was: (a) ρ = 0.95, (b) ρ = 0.96, and (c) could not be evaluated using this cohort. Future research should consider anesthetic agents when analyzing PVP waveforms developing future clinical monitoring technology that uses PVP.

The Sinotubular Junction-to-Aortic Annulus Ratio as a Determinant of Supravalvar Aortic Stenosis Severity.

Supravalvar aortic stenosis (SVAS) severity guides management, including decisions for surgery. Physiologic and technical factors limit the determination of SVAS severity by Doppler echocardiography and cardiac catheterization in Williams syndrome (WS). We hypothesized SVAS severity could be determined by the sinotubular junction-to-aortic annulus ratio (STJ:An). We reviewed all preintervention echocardiograms in patients with WS with SVAS cared for at our center. We measured STJ, An, peak and mean Doppler gradients, and calculated STJ:An. We created 2 mean gradient prediction models. Model 1 used the simplified Bernoulli's equation, and model 2 used computational fluid dynamics (CFD). We compared STJ:An to Doppler-derived and CFD gradients. We reviewed catheterization gradients and the waveforms and analyzed gradient variability. We analyzed 168 echocardiograms in 54 children (58% male, median age at scan 1.2 years, interquartile range [IQR] 0.5 to 3.6, median echocardiograms 2, IQR 1 to 4). Median SVAS peak Doppler gradient was 24 mm Hg (IQR 14 to 46.5). Median SVAS mean Doppler gradient was 11 mm Hg (IQR 6 to 21). Median STJ:An was 0.76 (IQR 0.63 to 0.84). Model 1 underpredicted clinical gradients. Model 2 correlated well with STJ:An through all severity ranges and demonstrated increased pressure recovery distance with decreased STJ:An. The median potential variability in catheterization-derived gradients in a given patient was 14.5 mm Hg (IQR 7.5 to 19.3). SVAS severity in WS can be accurately assessed using STJ:An. CFD predicts clinical data well through all SVAS severity levels. STJ:An is independent of physiologic state and has fewer technical limitations than Doppler echocardiography and catheterization. STJ:An could augment traditional methods in guiding surgical management decisions.

Suppressing Kv1.3 Ion Channel Activity with a Novel Small Molecule Inhibitor Ameliorates Inflammation in a Humanised Mouse Model of Ulcerative Colitis.

BACKGROUND AND AIMS: The potassium channel Kv1.3 is a potentially attractive therapeutic target in T cell-mediated inflammatory diseases, as the activity of antigen-activated T cells is selectively impeded by Kv1.3 inhibition. In this study, we examined Kv1.3 as a potential therapeutic intervention point for ulcerative colitis [UC], and studied the efficacy of DES1, a small-molecule inhibitor of Kv1.3, in vitro and in vivo. METHODS: Kv1.3 expression on T cells in peripheral blood mononuclear cells [PBMCs] isolated from donors with and without UC was examined by flow cytometry. In biopsies from UC patients, Kv1.3-expressing CD4+ T cells were detected by flow cytometry and immunohistochemistry. In vitro, we determined the ability of DES1 to inhibit anti-CD3-driven activation of T cells. In vivo, the efficacy of DES1 was determined in a humanised mouse model of UC and compared with infliximab and tofacitinib in head-to-head studies. RESULTS: Kv1.3 expression was elevated in PBMCs from UC patients and correlated with the prevalence of TH1 and TH2 T cells. Kv1.3 expression was also detected on T cells from biopsies of UC patients. In vitro, DES1 suppressed anti-CD3-driven activation of T cells in a concentration-dependent manner. In vivo, DES1 significantly ameliorated inflammation in the UC model and most effectively so when PBMCs from donors with higher levels of activated T cells were selected for reconstitution. The efficacy of DES1 was comparable to that of either infliximab or tofacitinib. CONCLUSION: Inhibition of Kv1.3 [by DES1, for instance] appears to be a potential therapeutic intervention strategy for UC patients.

Real-Time Transthoracic Vector Flow Imaging of the Heart in Pediatric Patients.

In children with congenital heart defects, Doppler ultrasound is the standard, bedside imaging modality. However, precise characterization of blood flow is challenging due to angle-dependent and one-dimensional velocity estimation. Contrast agent free Vector Flow Imaging is a new ultrasound technology that enables angle-independent visualization of the detailed flow field. Two piglets, one with normal cardiac anatomy and one with congenital heart disease comprised of valvular pulmonary stenosis, a dilated main pulmonary artery, and an incomplete atrioventricular canal defect, were imaged transthoracically and epicardially using a BK Ultrasound bk5000 with built-in vector flow imaging and a 5MHz linear probe. Subsequently, two children, one with normal cardiac anatomy and one with congenital heart disease comprised of aortic valve stenosis and coarctation of the aorta were imaged transthoracically. Transthoracic two-dimensional echocardiography and vector flow imaging were readily performed in both animals and were limited only by the geometry of the porcine thorax. In addition, transthoracic vector flow imaging was successfully performed in both children, and abnormal flow secondary to cardiac anomalies was visible. Adequate penetration was obtained to a depth of 6.5 cm. Our group has previously demonstrated for the first time that transthoracic vector flow imaging echocardiography is feasible and practicable in pediatric-sized patients, and this paper describes examples of these concepts and in-depth comparisons with traditional imaging modalities. This paper demonstrates that commercially available vector flow imaging technology can be utilized in pediatric cardiac applications as a bedside transthoracic imaging modality, providing advanced detail of blood flow patterns within the cardiac chambers, across valves, and in the great arteries.

Venous Physiology Predicts Dehydration in the Pediatric Population.

BACKGROUND: No standard dehydration monitor exists for children. This study attempts to determine the utility of Fast Fourier Transform (FFT) of a peripheral venous pressure (PVP) waveform to predict dehydration. MATERIALS AND METHODS: PVP waveforms were collected from 18 patients. Groups were defined as resuscitated (serum chloride ≥ 100 mmol/L) and hypovolemic (serum chloride < 100 mmol/L). Data were collected on emergency department admission and after a 20 cc/kg fluid bolus. The MATLAB (MathWorks) software analyzed nonoverlapping 10-s window signals; 2.4 Hz (144 bps) was the most demonstrative frequency to compare the PVP signal power (mmHg). RESULTS: Admission FFTs were compared between 10 (56%) resuscitated and 8 (44%) hypovolemic patients. The PVP signal power was higher in resuscitated patients (median 0.174 mmHg, IQR: 0.079-0.374 mmHg) than in hypovolemic patients (median 0.026 mmHg, IQR: 0.001-0.057 mmHg), (P < 0.001). Fourteen patients received a bolus regardless of laboratory values: 6 (43%) resuscitated and 8 (57%) hypovolemic. In resuscitated patients, the signal power did not change significantly after the fluid bolus (median 0.142 mmHg, IQR: 0.032-0.383 mmHg) (P = 0.019), whereas significantly increased signal power (median 0.0474 mmHg, IQR: 0.019-0.110 mmHg) was observed in the hypovolemic patients after a fluid bolus at 2.4 Hz (P < 0.001). The algorithm predicted dehydration for window-level analysis (sensitivity 97.95%, specificity 93.07%). The algorithm predicted dehydration for patient-level analysis (sensitivity 100%, specificity 100%). CONCLUSIONS: FFT of PVP waveforms can predict dehydration in hypertrophic pyloric stenosis. Further work is needed to determine the utility of PVP analysis to guide fluid resuscitation status in other pediatric populations.

New Mitral Valve Annuloplasty Concept: Optimizing Annular Dynamics and Force Distribution.

BACKGROUND: Temporal three-dimensional (3D) analysis of the mitral valve biomechanics has prompted a re-evaluation of surgical approaches and repair device designs to accommodate the natural dynamics of the valve. Such new designs strive to obtain lower annulus restraining forces, resulting in more natural leaflet and chordal stresses. A new annuloplasty system was evaluated using 3D motion and out-of-plane force analysis. It was hypothesized that this system would not impact the valve with adverse motion restrictions or high systolic annular forces compared to conventional flat rigid ring designs. METHODS: In an acute porcine set-up, six 80 kg pigs were monitored before and after implantation of the new annuloplasty system consisting of two half-rings with a saddle-shaped outline. Valvular 3D dynamic geometry was obtained using sonomicrometry before and after annuloplasty system implantation. Strain gauges mounted on the commissural segments provided the annular restraining force distribution perpendicular to the annular plane. RESULTS: The change in annular height to commissural width ratio from diastole to systole did not alter following implantation (p >0.05). Out-of-plane systolic restraining forces were 0.2 ± 0.1 N and 0.8 ± 0.3 N (mean ± SEM) in the posterior and anterior commissural segments, respectively, without any difference in-between (p >0.1). Forces in both commissural segments were significantly lowered compared to previous measurements with a flat and stiff mitral annuloplasty ring (p <0.01). Mitral annular septal-lateral distance, area, and circumference in the commissural segments were decreased after implantation (p <0.05). The cross-annular distance between the commissural segments and the lengths of the anterior and posterior annular segments did not change following implantation (p >0.05). CONCLUSIONS: The new annuloplasty system design maintained annular 3D dynamics and provided a minimized out-of-plane restraining force distribution compared to earlier studies on flat rigid rings. This may have important implications in the selection of annuloplasty devices in order to increase repair durability.

Mechanism of NMDA receptor channel block by MK-801 and memantine.

The NMDA (N-methyl-D-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel 1 . Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1-GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer's disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation.

Optimizing peripheral venous pressure waveforms in an awake pediatric patient by decreasing signal interference.

The purpose of this technological notes paper is to describe our institution's experience collecting peripheral venous pressure (PVP) waveforms using a standard peripheral intravenous catheter in an awake pediatric patient. PVP waveforms were collected from patients with hypertrophic pyloric stenosis. PVP measurements were obtained prospectively at two time points during the hospitalization: admission to emergency department and after bolus in emergency department. Data was collected from thirty-two patients. Interference in the PVP waveforms data collection was associated with the following: patient or device motion, system set-up error, type of IV catheter, and peripheral intravenous catheter location. PVP waveforms can be collected in an awake pediatric patient and adjuncts to decrease signal interference can be used to optimize data collection.

Remodeling Mitral Annuloplasty Ring Concept with Preserved Dynamics of Annular Height.

BACKGROUND AND AIM OF THE STUDY: The configuration of the native annulus changes from nearly flat in the diastolic phase to saddle-shaped in the systolic phase. The present study was conducted to test a novel remodeling annuloplasty ring with built-in septal-lateral fixation and commissural axial flexibility so as to maintain the change in annular saddle shape. The study aim was to evaluate the in-vivo biomechanical performance of the novel annuloplasty ring, compared with the native valve and a semi-rigid and rigid annuloplasty ring. METHODS: All measurements were performed in vivo using a porcine model. A total of 28 pigs (bodyweight ca. 80 kg) were randomized to four groups: (i) with no ring; (ii) with a novel remodeling ring; (iii) with a semi-rigid ring (Physio I Ring, Edwards Lifesciences); and (iv) with a rigid ring (Classic Annuloplasty Ring, Edwards Lifesciences). Force measurements were performed using a dedicated transducer to determine remodeling capacity of the annuloplasty rings. Geometric parameters were measured by implanting sonomicrometry crystals along the mitral annulus. RESULTS: All ring groups significantly restricted the cyclic change of the mitral annulus compared with the 'no-ring' group. The change and maximum value of the annular height were maintained for the novel ring but were significantly decreased for the rigid and semi-rigid rings compared with the 'no-ring' group. Mitral annular force measurements confirmed that the overall remodeling capacity of the novel ring was comparable with the conventional ring groups, and significantly higher in the septal-lateral direction compared to the semi-rigid ring. CONCLUSIONS: In-vivo geometry and force measurements indicated that the intended design features of the new device were successfully provided. The novel ring concept with remodeling properties, combined with the advantages of a flexible annuloplasty ring, is unique. The maintenance of annular saddle shape and cyclic change in annular height may be an important step towards improved mitral valve repair.

High resolution imaging of the mitral valve in the natural state with 7 Tesla MRI.

Imaging techniques of the mitral valve have improved tremendously during the last decade, but challenges persist. The delicate changes in annulus shape and papillary muscle position throughout the cardiac cycle have significant impact on the stress distribution in the leaflets and chords, thus preservation of anatomically accurate positioning is critical. The aim of this study was to develop an in vitro method and apparatus for obtaining high-resolution 3D MRI images of porcine mitral valves in both the diastolic and systolic configurations with physiologically appropriate annular shape, papillary muscle positions and orientations, specific to the heart from which the valve was harvested. Positioning and mounting was achieved through novel, customized mounting hardware consisting of papillary muscle and annulus holders with geometries determined via pre-mortem ultrasonic intra-valve measurements. A semi-automatic process was developed and employed to tailor Computer Aided Design models of the holders used to mount the valve. All valve mounting hardware was 3D printed using a stereolithographic printer, and the material of all fasteners used were brass for MRI compatibility. The mounted valves were placed within a clear acrylic case, capable of holding a zero-pressure and pressurized liquid bath of a MRI-compatible fluid. Obtaining images from the valve submerged in liquid fluid mimics the natural environment surrounding the valve, avoiding artefacts due to tissue surface tension mismatch and gravitational impact on tissue shape when not neutrally buoyant. Fluid pressure was supplied by reservoirs held at differing elevations and monitored and controlled to within ±1mmHg to ensure that the valves remained steady. The valves were scanned in a 7 Tesla MRI system providing a voxel resolution of at least 80µm. The systematic approach produced 3D datasets of high quality which, when combined with physiologically accurate positioning by the apparatus, can serve as an important input for validated computational models.