In-Vitro Pulsatile Flow Testing of Prosthetic Heart Valves: A Round-Robin Study by the ISO Cardiac Valves Working Group.

PURPOSE: Hydrodynamic performance testing is one of the core in vitro assessments required by the ISO 5840 series of standards for all prosthetic heart valves. A round-robin study carried out in 2005 in accordance with ISO 5840:2005 revealed significant variabilities in prosthetic heart valve hydrodynamic performance measurements among the participating laboratories. In order to re-examine the inter-laboratory variability based on the "state-of-the-art" under ISO 5840-1 and 5840-2:2015, the ISO Cardiac Valve Working Groups decided in 2016 to repeat the round-robin study. METHODS: A total of 13 international laboratories participated in the study. The test valves were chosen to be the St. Jude Medical Masters Series mechanical valves (19 mm aortic, 25 mm aortic, 25 mm mitral, and 31 mm mitral), which were circulated among the laboratories. The testing was conducted according to a common test run sequence, with prespecified flow conditions. RESULTS: The study revealed improved, yet still significant variability among different laboratories as compared to the 2005 study. The coefficient of variation ranged from 7.7 to 21.6% for the effective orifice area, from 10.1 to 32.8% for the total regurgitant fraction, and from 14.7 to 45.5% for the mean transvalvular pressure gradient. CONCLUSIONS: The study revealed the ambiguities in the current versions of the ISO 5840 series of standards and the shortcomings of some participating laboratories. This information has allowed the ISO Working Group to incorporate additional clarifying language into the ISO 5840-1, -2, and -3 standards that are currently under revision to improve in vitro assessments. The results presented here can also be used by the testing laboratories to benchmark pulse duplicator systems and to train and certify testing personnel.

Experimental Assessment of Flow Fields Associated with Heart Valve Prostheses Using Particle Image Velocimetry (PIV): Recommendations for Best Practices.

Experimental flow field characterization is a critical component of the assessment of the hemolytic and thrombogenic potential of heart valve substitutes, thus it is important to identify best practices for these experimental techniques. This paper presents a brief review of commonly used flow assessment techniques such as Particle image velocimetry (PIV), Laser doppler velocimetry, and Phase contrast magnetic resonance imaging and a comparison of these methodologies. In particular, recommendations for setting up planar PIV experiments such as recommended imaging instrumentation, acquisition and data processing are discussed in the context of heart valve flows. Multiple metrics such as residence time, local velocity and shear stress that have been identified in the literature as being relevant to hemolysis and thrombosis in heart valves are discussed. Additionally, a framework for uncertainty analysis and data reporting for PIV studies of heart valves is presented in this paper. It is anticipated that this paper will provide useful information for heart valve device manufacturers and researchers to assess heart valve flow fields for the potential for hemolysis and thrombosis.

Total ellipse of the heart valve: the impact of eccentric stent distortion on the regional dynamic deformation of pericardial tissue leaflets of a transcatheter aortic valve replacement.

Transcatheter aortic valve replacements (TAVRs) are a percutaneous alternative to surgical aortic valve replacements and are used to treat patients with aortic valve stenosis. This minimally invasive procedure relies on expansion of the TAVR stent to radially displace calcified aortic valve leaflets against the aortic root wall. However, these calcium deposits can impede the expansion of the device causing distortion of the valve stent and pericardial tissue leaflets. The objective of this study was to elucidate the impact of eccentric TAVR stent distortion on the dynamic deformation of the tissue leaflets of the prosthesis in vitro. Dual-camera stereophotogrammetry was used to measure the regional variation in strain in a leaflet of a TAVR deployed in nominal circular and eccentric (eccentricity index = 28%) orifices, representative of deployed TAVRs in vivo. It was observed that (i) eccentric stent distortion caused incorrect coaptation of the leaflets at peak diastole resulting in a 'peel-back' leaflet geometry that was not present in the circular valve and (ii) adverse bending of the leaflet, arising in the eccentric valve at peak diastole, caused significantly higher commissure strains compared with the circular valve in both normotensive and hypertensive pressure conditions (normotension: eccentric = 13.76 ± 2.04% versus circular = 11.77 ± 1.61%, p = 0.0014, hypertension: eccentric = 15.07 ± 1.13% versus circular = 13.56 ± 0.87%, p = 0.0042). This study reveals that eccentric distortion of a TAVR stent can have a considerable impact on dynamic leaflet deformation, inducing deleterious bending of the leaflet and increasing commissures strains, which might expedite leaflet structural failure compared to leaflets in a circular deployed valve.

Design of a pulsatile flow facility to evaluate thrombogenic potential of implantable cardiac devices.

Due to expensive nature of clinical trials, implantable cardiac devices should first be extensively characterized in vitro. Prosthetic heart valves (PHVs), an important class of these devices, have been shown to be associated with thromboembolic complications. Although various in vitro systems have been designed to quantify blood-cell damage and platelet activation caused by nonphysiological hemodynamic shear stresses in these PHVs, very few systems attempt to characterize both blood damage and fluid dynamics aspects of PHVs in the same test system. Various numerical modeling methodologies are also evolving to simulate the structural mechanics, fluid mechanics, and blood damage aspects of these devices. This article presents a completely hemocompatible small-volume test-platform that can be used for thrombogenicity studies and experimental fluid mechanics characterization. Using a programmable piston pump to drive freshly drawn human blood inside a cylindrical column, the presented system can simulate various physiological and pathophysiological conditions in testing PHVs. The system includes a modular device-mounting chamber, and in this presented case, a 23 mm St. Jude Medical (SJM) Regents® mechanical heart valve (MHV) in aortic position was used as the test device. The system was validated for its capability to quantify blood damage by measuring blood damage induced by the tester itself (using freshly drawn whole human blood). Blood damage levels were ascertained through clinically relevant assays on human blood while fluid dynamics were characterized using time-resolved particle image velocimetry (PIV) using a blood-mimicking fluid. Blood damage induced by the tester itself, assessed through Thrombin-anti-Thrombin (TAT), Prothrombin factor 1.2 (PF1.2), and hemolysis (Drabkins assay), was within clinically accepted levels. The hydrodynamic performance of the tester showed consistent, repeatable physiological pressure and flow conditions. In addition, the system contains proximity sensors to accurately capture leaflet motion during the entire cardiac cycle. The PIV results showed skewing of the leakage jet, caused by the asymmetric closing of the two leaflets. All these results are critical to characterizing the blood damage and fluid dynamics characteristics of the SJM Regents® MHV, proving the utility of this tester as a precise system for assessing the hemodynamics and thrombogenicity for various PHVs.

Bicuspid aortic valves are associated with increased wall and turbulence shear stress levels compared to trileaflet aortic valves.

Congenital bicuspid aortic valves (BAVs) are associated with accelerated disease progression, such as leaflet calcification and ascending aorta dilatation. Although common underlying genetic factors have been implicated in accelerated disease in BAV patients, several studies have suggested that altered hemodynamics also play a role in this disease process. The present study compares turbulence and wall shear stress (WSS) measurements between various BAV and trileaflet aortic valve (TAV) models to provide information for mechanobiological models of BAV disease. BAV and TAV models were constructed from excised porcine aortic valves to simulate parametric variations in BAV stenosis, hemodynamics and geometry. Particle image velocimetry experiments were conducted at physiological pressure conditions to characterize velocity fields in the ascending aorta. The velocity fields were post-processed to calculate turbulence, viscous and wall shear stresses in the ascending aorta. Stenosed BAV models showed the presence of eccentric systolic jets, causing increased WSS. Lower cardiac output resulted in a narrower jet, lower turbulence and lower viscous shear stress (VSS). The specific severe stenosis BAV model studied here showed reduced WSS due to reduction in non-fused leaflet mobility. Dilation of the aorta did not affect any turbulence or VSS, but reduced the WSS. In comparison with BAVs, TAVs have similar VSS values, but much smaller WSS and turbulence levels. These increased turbulence  and WSS levels in BAVs may play a key role in amplifying the biological responses of the ascending aorta wall and valvular leaflets, and support the hemodynamic underpinnings of BAV disease processes.

MRI-based Protocol to Characterize the Relationship Between Bicuspid Aortic Valve Morphology and Hemodynamics.

Bicuspid aortic valve (BAV) is the most common congenital heart defect and can lead to severe complications. Many studies have been conducted to evaluate the potential of geometric and hemodynamic biomarkers to predict BAV-related aortopathy. This work proposes a novel semi-automatic protocol to characterize geometry and hemodynamics of aorta and aortic valve based on 2D cine and 4D flow MRI data. The protocol was applied to 12 BAV and 12 control subjects. Statistical differences between the groups were identified and linear regression models were investigated to elucidate the potential of this protocol to investigate the risk of disease progression. Statistical differences between the groups were found for orifice eccentricity, aorta diameter, velocity, jet angle and flow displacement. Key findings of the regression analysis include the association in the proximal ascending aorta between aorta diameter and mean velocity (negative), jet angle (positive) and flow displacement (positive), in the combined cohort. Positive association between flow displacement in the proximal aorta and orifice jet angle in TAV subjects was found. This study represents a pilot application of a protocol for standardized assessment of aortic geometry and hemodynamics associated with BAV disease. Its limited need for user input is advantageous for large cohort studies.

Isolated effect of geometry on mitral valve function for in silico model development.

Computational models for the heart's mitral valve (MV) exhibit several uncertainties that may be reduced by further developing these models using ground-truth data-sets. This study generated a ground-truth data-set by quantifying the effects of isolated mitral annular flattening, symmetric annular dilatation, symmetric papillary muscle (PM) displacement and asymmetric PM displacement on leaflet coaptation, mitral regurgitation (MR) and anterior leaflet strain. MVs were mounted in an in vitro left heart simulator and tested under pulsatile haemodynamics. Mitral leaflet coaptation length, coaptation depth, tenting area, MR volume, MR jet direction and anterior leaflet strain in the radial and circumferential directions were successfully quantified at increasing levels of geometric distortion. From these data, increase in the levels of isolated PM displacement resulted in the greatest mean change in coaptation depth (70% increase), tenting area (150% increase) and radial leaflet strain (37% increase) while annular dilatation resulted in the largest mean change in coaptation length (50% decrease) and regurgitation volume (134% increase). Regurgitant jets were centrally located for symmetric annular dilatation and symmetric PM displacement. Asymmetric PM displacement resulted in asymmetrically directed jets. Peak changes in anterior leaflet strain in the circumferential direction were smaller and exhibited non-significant differences across the tested conditions. When used together, this ground-truth data-set may be used to parametrically evaluate and develop modelling assumptions for both the MV leaflets and subvalvular apparatus. This novel data may improve MV computational models and provide a platform for the development of future surgical planning tools.

Effect of hinge gap width of a St. Jude medical bileaflet mechanical heart valve on blood damage potential--an in vitro micro particle image velocimetry study.

The hinge regions of the bileaflet mechanical heart valve (BMHV) can cause blood element damage due to nonphysiological shear stress levels and regions of flow stasis. Recently, a micro particle image velocimetry (µPIV) system was developed to study whole flow fields within BMHV hinge regions with enhanced spatial resolution under steady leakage flow conditions. However, global velocity maps under pulsatile conditions are still necessary to fully understand the blood damage potential of these valves. The current study hypothesized that the hinge gap width will affect flow fields in the hinge region. Accordingly, the blood damage potential of three St. Jude Medical (SJM) BMHVs with different hinge gap widths was investigated under pulsatile flow conditions, using a µPIV system. The results demonstrated that the hinge gap width had a significant influence during the leakage flow phase in terms of washout and shear stress characteristics. During the leakage flow, the largest hinge gap generated the highest Reynolds shear stress (RSS) magnitudes (~1000 N/m²) among the three valves at the ventricular side of the hinge. At this location, all three valves indicated viscous shear stresses (VSS) greater than 30 N/m². The smallest hinge gap exhibited the lowest level of shear stress values, but had the poorest washout flow characteristics among the three valves, demonstrating propensity for flow stasis and associated activated platelet accumulation potential. The results from this study indicate that the hinge is a critical component of the BMHV design, which needs to be optimized to find the appropriate balance between reduction in fluid shear stresses and enhanced washout during leakage flow, to ensure minimal thrombotic complications.

An in vitro evaluation of the impact of eccentric deployment on transcatheter aortic valve hemodynamics.

Patients with aortic stenosis present with calcium deposits on the native aortic valve, which can result in non-concentric expansion of Transcatheter Aortic Valve Replacement (TAVR) stents. The objective of this study is to evaluate whether eccentric deployment of TAVRs lead to turbulent blood flow and blood cell damage. Particle Image Velocimetry was used to quantitatively characterize fluid velocity fields, shear stress and turbulent kinetic energy downstream of TAVRs deployed in circular and eccentric orifices representative of deployed TAVRs in vivo. Effective orifice area (EOA) and mean transvalvular pressure gradient (TVG) values did not differ substantially in circular and eccentric deployed valves, with only a minor decrease in EOA observed in the eccentric valve (2.0 cm(2) for circular, 1.9 cm(2) for eccentric). Eccentric deployed TAVR lead to asymmetric systolic jet formation, with increased shear stresses (circular = 97 N/m(2) vs. eccentric = 119 N/m(2)) and regions of turbulence intensity (circular = 180 N/m(2) vs. eccentric = 230 N/m(2)) downstream that was not present in the circular deployed TAVR. The results of this study indicate that eccentric deployment of TAVRs can lead to altered flow characteristics and may potentially increase the hemolytic potential of the valve, which were not captured through hemodynamic evaluation alone.

Micro particle image velocimetry measurements of steady diastolic leakage flow in the hinge of a St. Jude Medical® regent™ mechanical heart valve.

A number of clinical, in vitro and computational studies have shown the potential for thromboembolic complications in bileaflet mechanical heart valves (BMHV), primarily due to the complex and unsteady flows in the valve hinges. These studies have focused on quantitative and qualitative parameters such as velocity magnitude, turbulent shear stresses, vortex formation, and platelet activation to identify potential for blood damage. However, experimental characterization of the whole flow fields within the valve hinges has not yet been conducted. This information can be utilized to investigate instantaneous damage to blood elements and also to validate numerical studies focusing on the hinge's complex fluid dynamics. The objective of this study was therefore to develop a high-resolution imaging system to characterize the flow fields and global velocity maps in a BMHV hinge. In this study, the steady leakage hinge flow fields representing the diastolic phase during the cardiac cycle in a 23 mm St. Jude Medical regent BMHV in the aortic position were characterized using a two-dimensional micro particle image velocimetry system. Diastolic flow was simulated by imposing a static pressure head on the aortic side. Under these conditions, a reverse flow jet from the aortic to the ventricular side was observed with velocities in the range of 1.47-3.24 m/s, whereas low flow regions were observed on the ventricular side of the hinge with viscous shear stress magnitude up to 60 N/m². High velocities and viscous shearing may be associated with platelet activation and hemolysis, while low flow zones can cause thrombosis due to increased residence time in the hinge. Overall, this study provides a high spatial resolution experimental technique to map the fluid velocity in the BMHV hinge, which can be extended to investigate micron-scale flow domains in various prosthetic devices under different hemodynamic conditions.

In-vivo mitral annuloplasty ring transducer: implications for implantation and annular downsizing.

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.

In vitro comparison of Doppler and catheter-measured pressure gradients in 3D models of mitral valve calcification.

Mitral annular calcification (MAC) involves calcium deposition in the fibrous annulus supporting the mitral valve (MV). When calcification extends onto the leaflets, valve opening can be restricted. The influence of MAC MV geometry on Doppler gradients is unknown. This study describes a novel methodology to rapid-prototype subject-specific MAC MVs. Replicated valves were used to assess the effects of distorted annular-leaflet geometry on Doppler-derived, transmitral gradients in comparison to direct pressure measurements and to determine if transmitral gradients vary according to measurement location. Three-dimensional echocardiography data sets were selected for two MAC MVs and one healthy MV. These MVs were segmented and rapid prototyped in their middiastolic configuration for in vitro testing. The effects of MV geometry, measurement modality, and measurement location on transmitral pressure gradient were assessed by Doppler and catheter at three locations along the MV's intercommissural axis. When comparing dimensions of the rapid-prototyped valves to the subject echocardiography data sets, mean relative errors ranged from 6.2% to 35%. For the evaluated MVs, Doppler pressure gradients exhibited good agreement with catheter-measured gradients at a variety of flow rates, though with slight systematic overestimation in the recreated MAC valves. For all of the tested MVs, measuring the transmitral pressure gradient at differing valve orifice positions had minimal impact on observed gradients. Upon the testing of additional normal and calcific MVs, these data may contribute to an improved clinical understanding of MAC-related mitral stenosis. Moreover, they provide the ability to statistically evaluate between measurement locations, flow rates, and valve geometries for Doppler-derived pressure gradients. Determining these end points will contribute to greater clinical understanding for the diagnosis MAC patients and understanding the use and application of Doppler echocardiography to estimate transmitral pressure gradients.

Accuracy of a mitral valve segmentation method using J-splines for real-time 3D echocardiography data.

Patient-specific models of the heart's mitral valve (MV) exhibit potential for surgical planning. While advances in 3D echocardiography (3DE) have provided adequate resolution to extract MV leaflet geometry, no study has quantitatively assessed the accuracy of their modeled leaflets vs. a ground-truth standard for temporal frames beyond systolic closure or for differing valvular dysfunctions. The accuracy of a 3DE-based segmentation methodology based on J-splines was assessed for porcine MVs with known 4D leaflet coordinates within a pulsatile simulator during closure, peak closure, and opening for a control, prolapsed, and billowing MV model. For all time points, the mean distance error between the segmented models and ground-truth data were 0.40 ± 0.32 mm, 0.52 ± 0.51 mm, and 0.74 ± 0.69 mm for the control, flail, and billowing models. For all models and temporal frames, 95% of the distance errors were below 1.64 mm. When applied to a patient data set, segmentation was able to confirm a regurgitant orifice and post-operative improvements in coaptation. This study provides an experimental platform for assessing the accuracy of an MV segmentation methodology at phases beyond systolic closure and for differing MV dysfunctions. Results demonstrate the accuracy of a MV segmentation methodology for the development of future surgical planning tools.

Mechanics of healthy and functionally diseased mitral valves: a critical review.

The mitral valve is a complex apparatus with multiple constituents that work cohesively to ensure unidirectional flow between the left atrium and ventricle. Disruption to any or all of the components-the annulus, leaflets, chordae, and papillary muscles-can lead to backflow of blood, or regurgitation, into the left atrium, which deleteriously effects patient health. Through the years, a myriad of surgical repairs have been proposed; however, a careful appreciation for the underlying structural mechanics can help optimize long-term repair durability and inform medical device design. In this review, we aim to present the experimental methods and significant results that have shaped the current understanding of mitral valve mechanics. Data will be presented for all components of the mitral valve apparatus in control, pathological, and repaired conditions from human, animal, and in vitro studies. Finally, current strategies of patient specific and noninvasive surgical planning will be critically outlined.

In vitro mitral valve simulator mimics systolic valvular function of chronic ischemic mitral regurgitation ovine model.

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.