Julia C. Swanson

Material properties of the ovine mitral valve anterior leaflet in vivo from inverse finite element analysis

We measured leaflet displacements and used inverse finite-element analysis to define, for the first time, the material properties of mitral valve (MV) leaflets in vivo. Sixteen miniature radiopaque markers were sewn to the MV annulus, 16 to the anterior MV leaflet, and 1 on each papillary muscle tip in 17 sheep. Four-dimensional coordinates were obtained from biplane videofluoroscopic marker images (60 frames/s) during three complete cardiac cycles. A finite-element model of the anterior MV leaflet was developed using marker coordinates at the end of isovolumic relaxation (IVR; when the pressure difference across the valve is approximately 0), as the minimum stress reference state. Leaflet displacements were simulated during IVR using measured left ventricular and atrial pressures. The leaflet shear modulus (G(circ-rad)) and elastic moduli in both the commisure-commisure (E(circ)) and radial (E(rad)) directions were obtained using the method of feasible directions to minimize the difference between simulated and measured displacements. Group mean (+/-SD) values (17 animals, 3 heartbeats each, i.e., 51 cardiac cycles) were as follows: G(circ-rad) = 121 +/- 22 N/mm2, E(circ) = 43 +/- 18 N/mm2, and E(rad) = 11 +/- 3 N/mm2 (E(circ) > E(rad), P < 0.01). These values, much greater than those previously reported from in vitro studies, may result from activated neurally controlled contractile tissue within the leaflet that is inactive in excised tissues. This could have important implications, not only to our understanding of mitral valve physiology in the beating heart but for providing additional information to aid the development of more durable tissue-engineered bioprosthetic valves.

Stress-Strain Behavior of Mitral Valve Leaflets in the Beating Ovine Heart

Excised anterior mitral leaflets exhibit anisotropic, non-linear material behavior with pre-transitional stiffness ranging from 0.06 to 0.09 N/mm(2) and post-transitional stiffness from 2 to 9 N/mm(2). We used inverse finite element (FE) analysis to test, for the first time, whether the anterior mitral leaflet (AML), in vivo, exhibits similar non-linear behavior during isovolumic relaxation (IVR). Miniature radiopaque markers were sewn to the mitral annulus, AML, and papillary muscles in 8 sheep. Four-dimensional marker coordinates were obtained using biplane videofluoroscopic imaging during three consecutive cardiac cycles. A FE model of the AML was developed using marker coordinates at the end of isovolumic relaxation (when pressure difference across the valve is approximately zero), as the reference state. AML displacements were simulated during IVR using measured left ventricular and atrial pressures. AML elastic moduli in the radial and circumferential directions were obtained for each heartbeat by inverse FEA, minimizing the difference between simulated and measured displacements. Stress-strain curves for each beat were obtained from the FE model at incrementally increasing transmitral pressure intervals during IVR. Linear regression of 24 individual stress-strain curves (8 hearts, 3 beats each) yielded a mean (+/-SD) linear correlation coefficient (r(2)) of 0.994+/-0.003 for the circumferential direction and 0.995+/-0.003 for the radial direction. Thus, unlike isolated leaflets, the AML, in vivo, operates linearly over a physiologic range of pressures in the closed mitral valve.

Mitral Valve Annuloplasty A Quantitative Clinical and Mechanical Comparison of Different Annuloplasty Devices

Mitral valve annuloplasty is a common surgical technique used in the repair of a leaking valve by implanting an annuloplasty device. To enhance repair durability, these devices are designed to increase leaflet coaptation, while preserving the native annular shape and motion; however, the precise impact of device implantation on annular deformation, strain, and curvature is unknown. In this article, we quantify how three frequently used devices significantly impair native annular dynamics. In controlled in vivo experiments, we surgically implanted 11 flexible-incomplete, 11 semi-rigid-complete, and 12 rigid-complete devices around the mitral annuli of 34 sheep, each tagged with 16 equally spaced tantalum markers. We recorded four-dimensional marker coordinates using biplane videofluoroscopy, first with device and then without, which were used to create mathematical models using piecewise cubic splines. Clinical metrics (characteristic anatomical distances) revealed significant global reduction in annular dynamics upon device implantation. Mechanical metrics (strain and curvature fields) explained this reduction via a local loss of anterior dilation and posterior contraction. Overall, all three devices unfavorably caused reduction in annular dynamics. The flexible-incomplete device, however, preserved native annular dynamics to a larger extent than the complete devices. Heterogeneous strain and curvature profiles suggest the need for heterogeneous support, which may spawn more rational design of annuloplasty devices using design concepts of functionally graded materials.

Active stiffening of mitral valve leaflets in the beating heart.

The anterior leaflet of the mitral valve (MV), viewed traditionally as a passive membrane, is shown to be a highly active structure in the beating heart. Two types of leaflet contractile activity are demonstrated: 1) a brief twitch at the beginning of each beat (reflecting contraction of myocytes in the leaflet in communication with and excited by left atrial muscle) that is relaxed by midsystole and whose contractile activity is eliminated with beta-receptor blockade and 2) sustained tone during isovolumic relaxation, insensitive to beta-blockade, but doubled by stimulation of the neurally rich region of aortic-mitral continuity. These findings raise the possibility that these leaflets are neurally controlled tissues, with potentially adaptive capabilities to meet the changing physiological demands on the heart. They also provide a basis for a permanent paradigm shift from one viewing the leaflets as passive flaps to one viewing them as active tissues whose complex function and dysfunction must be taken into account when considering not only therapeutic approaches to MV disease, but even the definitions of MV disease itself.

Characterization of mitral valve annular dynamics in the beating heart

The objective of this study is to establish a mathematical characterization of the mitral valve annulus that allows a precise qualitative and quantitative assessment of annular dynamics in the beating heart. We define annular geometry through 16 miniature markers sewn onto the annuli of 55 sheep. Using biplane videofluoroscopy, we record marker coordinates in vivo. By approximating these 16 marker coordinates through piecewise cubic splines, we generate a smooth mathematical representation of the 55 mitral annuli. We time-align these 55 annulus representations with respect to characteristic hemodynamic time points to generate an averaged baseline annulus representation. To characterize annular physiology, we extract classical clinical metrics of annular form and function throughout the cardiac cycle. To characterize annular dynamics, we calculate displacements, strains, and curvature from the discrete mathematical representations. To illustrate potential future applications of this approach, we create rapid prototypes of the averaged mitral annulus at characteristic hemodynamic time points. In summary, this study introduces a novel mathematical model that allows us to identify temporal, regional, and inter-subject variations of clinical and mechanical metrics that characterize mitral annular form and function. Ultimately, this model can serve as a valuable tool to optimize both surgical and interventional approaches that aim at restoring mitral valve competence.

Rigid, Complete Annuloplasty Rings Increase Anterior Mitral Leaflet Strains in the Normal Beating Ovine Heart

Background— Annuloplasty ring or band implantation during surgical mitral valve repair perturbs mitral annular dimensions, dynamics, and shape, which have been associated with changes in anterior mitral leaflet (AML) strain patterns and suboptimal long-term repair durability. We hypothesized that rigid rings with nonphysiological three-dimensional shapes, but not saddle-shaped rigid rings or flexible bands, increase AML strains. Methods and Results— Sheep had 23 radiopaque markers inserted: 7 along the anterior mitral annulus and 16 equally spaced on the AML. True-sized Cosgrove-Edwards flexible, partial band (n=12), rigid, complete St Jude Medical rigid saddle-shaped (n=12), Carpentier-Edwards Physio (n=12), Edwards IMR ETlogix (n=11), and Edwards GeoForm (n=12) annuloplasty rings were implanted in a releasable fashion. Under acute open-chest conditions, 4-dimensional marker coordinates were obtained using biplane videofluoroscopy along with hemodynamic parameters with the ring inserted and after release. Marker coordinates were triangulated, and the largest maximum principal AML strains were determined during isovolumetric relaxation. No relevant changes in hemodynamics occurred. Compared with the respective control state, strains increased significantly with rigid saddle-shaped annuloplasty ring, Carpentier-Edwards Physio, Edwards IMR ETlogix, and Edwards GeoForm (0.14±0.05 versus 0.16±0.05, P=0.024, 0.15±0.03 versus 0.18±0.04, P=0.020, 0.11±0.05 versus 0.14±0.05, P=0.042, and 0.13±0.05 versus 0.16±0.05, P=0.009), but not with Cosgrove-Edwards band (0.15±0.05 versus 0.15±0.04, P=0.973). Conclusions— Regardless of three-dimensional shape, rigid, complete annuloplasty rings, but not a flexible, partial band, increased AML strains in the normal beating ovine heart. Clinical studies are needed to determine whether annuloplasty rings affect AML strains in patients, and, if so, whether ring-induced perturbations in leaflet strain states are linked to repair failure.

Mitral leaflet modeling: Importance of in vivo shape and material properties

The anterior mitral leaflet (AML) is a thin membrane that withstands high left ventricular (LV) pressure pulses 100,000 times per day. The presence of contractile cells determines AML in vivo stiffness and complex geometry. Until recently, mitral valve finite element (FE) models have neglected both of these aspects. In this study we assess their effect on AML strains and stresses, hypothesizing that these will differ significantly from those reported in literature. Radiopaque markers were sewn on the LV, the mitral annulus, and AML in sheep hearts, and their four-dimensional coordinates obtained with biplane video fluoroscopy. Employing in vivo data from three representative hearts, AML FE models were created from the marker coordinates at the end of isovolumic relaxation assumed as the unloaded reference state. AML function was simulated backward through systole, applying the measured trans-mitral pressure on AML LV surface and marker displacements on AML boundaries. Simulated AML displacements and curvatures were consistent with in vivo measurements, confirming model accuracy. AML circumferential strains were mostly tensile (1-3%), despite being compressive (-1%) near the commissures. Radial strains were compressive in the belly (-1 to -0.2%), and tensile (2-8%) near the free edge. These results differ significantly from those of previous FE models. They reflect the synergy of high tissue stiffness, which limits tensile circumferential strains, and initial compound curvature, which forces LV pressure to compress AML radially. The obtained AML shape may play a role not only in preventing mitral regurgitation, but also in optimizing LV outflow fluid dynamics.

Regional stiffening of the mitral valve anterior leaflet in the beating ovine heart

Left atrial muscle extends into the proximal third of the mitral valve (MV) anterior leaflet and transient tensing of this muscle has been proposed as a mechanism aiding valve closure. If such tensing occurs, regional stiffness in the proximal anterior mitral leaflet will be greater during isovolumic contraction (IVC) than isovolumic relaxation (IVR) and this regional stiffness difference will be selectively abolished by beta-receptor blockade. We tested this hypothesis in the beating ovine heart. Radiopaque markers were sewn around the MV annulus and on the anterior MV leaflet in 10 sheep hearts. Four-dimensional marker coordinates were obtained from biplane videofluoroscopy before (CRTL) and after administration of esmolol (ESML). Heterogeneous finite element models of each anterior leaflet were developed using marker coordinates over matched pressures during IVC and IVR for CRTL and ESML. Leaflet displacements were simulated using measured left ventricular and atrial pressures and a response function was computed as the difference between simulated and measured displacements. Circumferential and radial elastic moduli for ANNULAR, BELLY and EDGE leaflet regions were iteratively varied until the response function reached a minimum. The stiffness values at this minimum were interpreted as the in vivo regional material properties of the anterior leaflet. For all regions and all CTRL beats IVC stiffness was 40-58% greater than IVR stiffness. ESML reduced ANNULAR IVC stiffness to ANNULAR IVR stiffness values. These results strongly implicate transient tensing of leaflet atrial muscle during IVC as the basis of the ANNULAR IVC-IVR stiffness difference.

How do annuloplasty rings affect mitral leaflet dynamic motion

OBJECTIVES To define the effects of annuloplasty rings (ARs) on the dynamic motion of anterior mitral leaflet (AML) and posterior mitral leaflet (PML). METHODS Fifty-eight adult, Dorsett-hybrid, male sheep (49 + or - 5 kg) had radiopaque markers inserted: eight around the mitral annulus, four along the central meridian (from edge to annulus) of the AML (#A(1)-#A(4)) and one on the PML edge (#P(1)). True-sized Edwards Cosgrove (COS, n=12), St Jude RSAR (St. Jude Medical, St. Paul, MN, USA) (n=12), Carpentier-Edwards Physio (PHYSIO, n=12), Edwards IMR ETlogix (ETL, n=10) or Edwards GeoForm (GEO, n=12) ARs were implanted in a releasable fashion. Under acute open-chest conditions, 4D marker coordinates were obtained using biplane videofluoroscopy with the respective AR inserted (COS, RSAR, PHYSIO, ETL and GEO) and after release (COS-Control, RSAR-Control, PHYSIO-Control, ETL-Control and GEO-Control). AML and PML excursions were calculated as the difference between minimum and maximum angles between the central mitral annular septal-lateral chord and the AML edge markers (alpha(1exc)-alpha(4exc)) and PML edge marker (beta(1exc)) during the cardiac cycle. RESULTS Relative to Control, (1) RSAR, PHYSIO, ETL and GEO increased excursion of the AML annular (alpha(4exc): 13 + or - 6 degrees vs 16 + or - 7 degrees *, 16 + or - 7 degrees vs 23 + or - 10 degrees *, 12 + or - 4 degrees vs 18 + or - 9 degrees *, 15 + or - 1 degrees vs 20 + or - 9 degrees *, respectively) and belly region (alpha(2exc): 41 + or - 10 degrees vs 45 + or - 10 degrees *, 42 + or - 8 degrees vs 45 + or - 6 degrees , n.s., 33 + or - 13 degrees vs 42 + or - 14 degrees *, 39 + or - 6 degrees vs 44 + or - 6 degrees *, respectively, alpha(3exc): 24 + or - 9 degrees vs 29 + or - 11 degrees *, 28 + or - 10 degrees vs 33 + or - 10 degrees *, 16 + or - 9 degrees vs 21 + or - 12 degrees *, 25 + or - 7 degrees vs 29 + or - 9 degrees *, respectively), but not of the AML edge (alpha(1exc): 42 + or - 8 degrees vs 44 + or - 8 degrees , 43 + or - 8 degrees vs 41 + or - 6 degrees , 42 + or - 11 vs 46 + or - 10 degrees , 39 + or - 9 degrees vs 38 + or - 8 degrees , respectively, all n.s.). COS did not affect AML excursion (alpha(1exc): 40 + or - 8 degrees vs 37 + or - 8 degrees , alpha(2exc): 43 + or - 9 degrees vs 41 + or - 9 degrees , alpha(3exc): 27 + or - 11 degrees vs 27 + or - 10 degrees , alpha(4exc): 18 + or - 8 degrees vs 17 + or - 7 degrees , all n.s.). (2) PML excursion (beta(1exc)) was reduced with GEO (53 + or - 5 degrees vs 43 + or - 6 degrees *), but unchanged with COS, RSAR, PHYSIO or ETL (53 + or - 13 degrees vs 52 + or - 15 degrees , 50 + or - 13 degrees vs 49 + or - 10 degrees , 55 + or - 5 degrees vs 55 + or - 7 degrees , 52 + or - 8 degrees vs 58 + or - 6 degrees , respectively, all n.s); *=p<0.05. CONCLUSIONS RSAR, PHYSIO, ETL and GEO rings, but not COS, increase AML excursion of the AML annular and belly region, suggesting higher anterior mitral leaflet bending stresses with rigid rings, which potentially could be deleterious with respect to repair durability. The decreased PML excursion observed with GEO could impair left ventricular filling. Clinical studies are needed to validate these findings in patients.

Anterior Mitral Leaflet Curvature During the Cardiac Cycle in the Normal Ovine Heart

Background— The dynamic changes of anterior mitral leaflet (AML) curvature are of primary importance for optimal left ventricular filling and emptying but are incompletely characterized. Methods and Results— Sixteen radiopaque markers were sutured to the AML in 11 sheep, and 4-dimensional marker coordinates were acquired with biplane videofluoroscopy. A surface subdivision algorithm was applied to compute the curvature across the AML at midsystole and at maximal valve opening. Septal-lateral (SL) and commissure-commissure (CC) curvature profiles were calculated along the SL AML meridian (MSL)and CC AML meridian (MCC), respectively, with positive curvature being concave toward the left atrium. At midsystole, the MSL was concave near the mitral annulus, turned from concave to convex across the belly, and was convex along the free edge. At maximal valve opening, the MSL was flat near the annulus, turned from slightly concave to convex across the belly, and flattened toward the free edge. In contrast, the MCC was concave near both commissures and convex at the belly at midsystole but convex near both commissures and concave at the belly at maximal valve opening. Conclusions— While the SL curvature of the AML along the MSL is similar across the belly region at midsystole and early diastole, the CC curvature of the AML along the MCC flips, with the belly being convex to the left atrium at midsystole and concave at maximal valve opening. These curvature orientations suggest optimal left ventricular inflow and outflow shapes of the AML and should be preserved during catheter or surgical interventions.