Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging.

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction.

Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

Ten years of implementation outcomes research: a scoping review.

BACKGROUND: Proctor and colleagues' 2011 paper proposed a taxonomy of eight implementation outcomes and challenged the field to address a research agenda focused on conceptualization, measurement, and theory building. Ten years later, this paper maps the field's progress in implementation outcomes research. This scoping review describes how each implementation outcome has been studied, research designs and methods used, and the contexts and settings represented in the current literature. We also describe the role of implementation outcomes in relation to implementation strategies and other outcomes. METHODS: Arksey and O'Malley's framework for conducting scoping reviews guided our methods. Using forward citation tracing, we identified all literature citing the 2011 paper. We conducted our search in the Web of Science (WOS) database and added citation alerts sent to the first author from the publisher for a 6-month period coinciding with the WOS citation search. This produced 1346 titles and abstracts. Initial abstract screening yielded 480 manuscripts, and full-text review yielded 400 manuscripts that met inclusion criteria (empirical assessment of at least one implementation outcome). RESULTS: Slightly more than half (52.1%) of included manuscripts examined acceptability. Fidelity (39.3%), feasibility (38.6%), adoption (26.5%), and appropriateness (21.8%) were also commonly examined. Penetration (16.0%), sustainability (15.8%), and cost (7.8%) were less frequently examined. Thirty-two manuscripts examined implementation outcomes not included in the original taxonomy. Most studies took place in healthcare (45.8%) or behavioral health (22.5%) organizations. Two-thirds used observational designs. We found little evidence of progress in testing the relationships between implementation strategies and implementation outcomes, leaving us ill-prepared to know how to achieve implementation success. Moreover, few studies tested the impact of implementation outcomes on other important outcome types, such as service systems and improved individual or population health. CONCLUSIONS: Our review presents a comprehensive snapshot of the research questions being addressed by existing implementation outcomes literature and reveals the need for rigorous, analytic research and tests of strategies for attaining implementation outcomes in the next 10 years of outcomes research.

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.

Contribution of myocardium overlying the anterolateral papillary muscle to left ventricular deformation.

Previous studies of transmural left ventricular (LV) strains suggested that the myocardium overlying the papillary muscle displays decreased deformation relative to the anterior LV free wall or significant regional heterogeneity. These comparisons, however, were made using different hearts. We sought to extend these studies by examining three equatorial LV regions in the same heart during the same heartbeat. Therefore, deformation was analyzed from transmural beadsets placed in the equatorial LV myocardium overlying the anterolateral papillary muscle (PAP), as well as adjacent equatorial LV regions located more anteriorly (ANT) and laterally (LAT). We found that the magnitudes of LAT normal longitudinal and radial strains, as well as major principal strains, were less than ANT, while those of PAP were intermediate. Subepicardial and midwall myofiber angles of LAT, PAP, and ANT were not significantly different, but PAP subendocardial myofiber angles were significantly higher (more longitudinal as opposed to circumferential orientation). Subepicardial and midwall myofiber strains of ANT, PAP, and LAT were not significantly different, but PAP subendocardial myofiber strains were less. Transmural gradients in circumferential and radial normal strains, and major principal strains, were observed in each region. The two main findings of this study were as follows: 1) PAP strains are largely consistent with adjacent LV equatorial free wall regions, and 2) there is a gradient of strains across the anterolateral equatorial left ventricle despite similarities in myofiber angles and strains. These findings point to graduated equatorial LV heterogeneity and suggest that regional differences in myofiber coupling may constitute the basis for such heterogeneity.

Six practical recommendations for improved implementation outcomes reporting.

BACKGROUND: Implementation outcomes research spans an exciting mix of fields, disciplines, and geographical space. Although the number of studies that cite the 2011 taxonomy has expanded considerably, the problem of harmony in describing outcomes persists. This paper revisits that problem by focusing on the clarity of reporting outcomes in studies that examine them. Published recommendations for improved reporting and specification have proven to be an important step in enhancing the rigor of implementation research. We articulate reporting problems in the current implementation outcomes literature and describe six practical recommendations that address them. RECOMMENDATIONS: Our first recommendation is to clearly state each implementation outcome and provide a definition that the study will consistently use. This includes providing an explanation if using the taxonomy in a new way or merging terms. Our second recommendation is to specify how each implementation outcome will be analyzed relative to other constructs. Our third recommendation is to specify "the thing" that each implementation outcome will be measured in relation to. This is especially important if you are concurrently studying interventions and strategies, or if you are studying interventions and strategies that have multiple components. Our fourth recommendation is to report who will provide data and the level at which data will be collected for each implementation outcome, and to report what kind of data will be collected and used to assess each implementation outcome. Our fifth recommendation is to state the number of time points and frequency at which each outcome will be measured. Our sixth recommendation is to state the unit of observation and the level of analysis for each implementation outcome. CONCLUSION: This paper advances implementation outcomes research in two ways. First, we illustrate elements of the 2011 research agenda with concrete examples drawn from a wide swath of current literature. Second, we provide six pragmatic recommendations for improved reporting. These recommendations are accompanied by an audit worksheet and a list of exemplar articles that researchers can use when designing, conducting, and assessing implementation outcomes studies.

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 (M(SL))and CC AML meridian (M(CC)), respectively, with positive curvature being concave toward the left atrium. At midsystole, the M(SL) 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 M(SL) was flat near the annulus, turned from slightly concave to convex across the belly, and flattened toward the free edge. In contrast, the M(CC) 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 M(SL) is similar across the belly region at midsystole and early diastole, the CC curvature of the AML along the M(CC) 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.

Electromechanical coupling between the atria and mitral valve.

Anterior leaflet (AL) stiffening during isovolumic contraction (IVC) may aid mitral valve closure. We tested the hypothesis that AL stiffening requires atrial depolarization. Ten sheep had radioopaque-marker arrays implanted in the left ventricle, mitral annulus, AL, and papillary muscle tips. Four-dimensional marker coordinates (x, y, z, and t) were obtained from biplane videofluoroscopy at baseline (control, CTRL) and during basal interventricular-septal pacing (no atrial contraction, NAC; 110-117 beats/min) to generate ventricular depolarization not preceded by atrial depolarization. Circumferential and radial stiffness values, reflecting force generation in three leaflet regions (annular, belly, and free-edge), were obtained from finite-element analysis of AL displacements in response to transleaflet pressure changes during both IVC and isovolumic relaxation (IVR). In CTRL, IVC circumferential and radial stiffness was 46 ± 6% greater than IVR stiffness in all regions (P < 0.001). In NAC, AL annular IVC stiffness decreased by 25% (P = 0.004) in the circumferential and 31% (P = 0.005) in the radial directions relative to CTRL, without affecting edge stiffness. Thus AL annular stiffening during IVC was abolished when atrial depolarization did not precede ventricular systole, in support of the hypothesis. The likely mechanism underlying AL annular stiffening during IVC is contraction of cardiac muscle that extends into the leaflet and requires atrial excitation. The AL edge has no cardiac muscle, and thus IVC AL edge stiffness was not affected by loss of atrial depolarization. These findings suggest one reason why heart block, atrial dysrhythmias, or ventricular pacing may be accompanied by mitral regurgitation or may worsen regurgitation when already present.

Transient stiffening of mitral valve leaflets in the beating heart.

Anterior mitral leaflet stiffness during isovolumic contraction (IVC) is much greater than that during isovolumic relaxation (IVR). We have hypothesized that this stiffening is due to transient early systolic force development in the slip of cardiac myocytes in the annular third of the anterior leaflet. Because the atrium is excited before IVC and leaflet myocytes contract for < or = 250 ms, this hypothesis predicts that IVC leaflet stiffness will drop to near-IVR values in the latter half of ventricular systole. We tested this prediction using radiopaque markers and inverse finite element analysis of 30 beats in 10 ovine hearts. For each beat, circumferential (E(c)) and radial (E(r)) stiffness was determined during IVC (Deltat(1)), end IVC to midsystole (Deltat(2)), midsystole to IVR onset (Deltat(3)), and IVR (Deltat(4)). Group mean stiffness (E(c) + or - SD; E(r) + or - SD; in N/mm(2)) during Deltat(1) (44 + or - 16; 15 + or - 4) was 1.6-1.7 times that during Deltat(4) (28 + or - 11; 9 + or - 3); Deltat(2) stiffness (39 + or - 15; 14 + or - 4) was 1.3-1.5 times that of Deltat(4), but Deltat(3) stiffness (32 + or - 12; 11 + or - 3) was only 1.1-1.2 times that of Deltat(4). The stiffness drop during Deltat(3) supports the hypothesis that anterior leaflet stiffening during IVC arises primarily from transient force development in leaflet cardiac myocytes, with stiffness reduced as this leaflet muscle relaxes in the latter half of ventricular systole.

Diaphragmatic Hernia Associated With Absent Ductus Venosus and Anomalous Connection of an Obliterated Umbilical Vein to the Coronary Sinus.

Umbilical vein anomalies are a rare congenital defect, which have been associated with absent ductus venosus, with few cases also involving a congenital diaphragmatic hernia. We describe a case of postnatal development of an anterior diaphragmatic hernia of Morgagni in a four-year-old patient diagnosed prenatally with mesocardia, absent ductus venosus with a large umbilical vein, a large secundum atrial septal defect, and patent ductus arteriosus.

Characterization of mitral valve anterior leaflet perfusion patterns.

BACKGROUND AND AIM OF THE STUDY: Although previous histologic studies have demonstrated the presence of blood vessels in the anterior mitral leaflet (AML) and second-order chordae (SC), little is known of the pattern of leaflet perfusion. Hence, the pattern and source of AML perfusion was investigated in an ovine model. METHODS: Fluorescein angiograms were obtained in 17 ovine hearts immediately after heparinization and cardioplegic arrest, using non-selective left coronary artery (LCA) and selective left anterior descending (LAD), proximal, mid- and distal left circumflex (LCx) perfusion. Serial photographs using a flash/filter system to optimize fluorescence were obtained through a left atriotomy. RESULTS: The proximal half of the AML was seen to be richly vascularized. A loop of vessels was consistently observed in the mitral annulus and AML; these vessels ran along the annulus, extended to the sites of SC insertion, and created anastomoses between these insertions. The SC contributed to the AML perfusion and the anastomotic loop. Selective perfusion of the LAD or proximal LCx artery (ligated before the first obtuse marginal artery) did not perfuse the AML (n = 6). Perfusion of the mid- and distal LCx (n = 7) consistently supplied the AML via SC insertion sites and annular branches. CONCLUSION: The ovine AML is perfused by vessels that run through the SC and annulus simultaneously, and then create a communicating arcade in the leaflet. These vessels originate from the mid- and distal portions of the LCx. A loss of perfusion as a result of microvascular disease could have adverse implications. Derangements in the extensive vascular component of the mitral valve could be an important contributing factor to valve disease.

Do annuloplasty rings designed to treat ischemic/functional mitral regurgitation alter left-ventricular dimensions in the acutely ischemic ovine heart?

OBJECTIVE: To quantify the effects of annuloplasty rings designed to treat ischemic/functional mitral regurgitation on left ventricular septal-lateral (S-L) and commissure-commissure (C-C) dimensions. METHODS: Radiopaque markers were placed as opposing pairs on the S-L and C-C aspects of the mitral annulus and the basal, equatorial, and apical level of the left ventricle (LV) in 30 sheep. Ten true-sized Carpentier-Edwards Physio (PHY), Edwards IMR ETlogix (ETL), and GeoForm (GEO; all from Edwards Lifesciences, Irvine, Calif) annuloplasty rings were inserted in a releasable fashion. After 90 seconds of left circumflex artery occlusion with the ring implanted (RING), 4-dimensional marker coordinates were obtained using biplane videofluoroscopy. After ring release, another data set was acquired after another 90 seconds of left circumflex artery occlusion (NO RING). S-L and C-C diameters were computed as the distances between the respective marker pairs at end-diastole. Percent change in diameters was calculated between RING versus NO RING as 100 × (diameter in centimeters [RING] - diameter in centimeters [NO RING])/diameter in centimeters [NO RING]). RESULTS: Compared with NO RING, all ring types (PHY, ETL, and GEO) reduced mitral annular S-L dimensions by -20.7 ± 5.6%, -26.8 ± 3.9%, and -34.5 ± 3.8%, respectively. GEO reduced the S-L dimensions of the LV at the basal level only by -2.3 ± 2.4%, whereas all other S-L dimensions of the LV remained unchanged with all 3 rings implanted. PHY, ETL, and GEO reduced mitral annular C-C dimensions by -17.5 ± 4.8%, -19.6 ± 2.5, and -8.3 ± 4.9%, respectively, but none of the rings altered the C-C dimensions of the LV. CONCLUSIONS: Despite radical reduction of mitral annular size, disease-specific ischemic/functional mitral regurgitation annuloplasty rings do not induce relevant changes of left ventricular dimensions in the acutely ischemic ovine heart.

Excision of an intrapericardial immature teratoma in a 26-week premature neonate.

We present a case of a 26 week premature newborn with an immature intrapericardial teratoma. The patient was transferred from an outside hospital for management of a large mediastinal mass causing respiratory insufficiency. The newborn was supported with the help of a large interdisciplinary team until day of life 22 when he underwent surgical excision. On follow up the infant is doing very well and is one of the youngest survivors to date.

Tissue Doppler-derived myocardial acceleration for evaluation of left ventricular diastolic function.

OBJECTIVES: Our purpose was to evaluate a tissue Doppler-based index-peak myocardial acceleration (pACC)-during isovolumic relaxation and in evaluating left ventricular (LV) diastolic function. BACKGROUND: Simple, practical indexes for diastolic function evaluation are lacking, but are much desired for clinical evaluation. METHODS: We examined eight sheep by using tissue Doppler ultrasound images obtained in the apical four-chamber views to evaluate mitral valve annular velocity at the septum and LV wall. The pACC thus derived was analyzed during isovolumic relaxation (IVRT) and during the LV filling period (LVFP). We then changed the hemodynamic status of each animal by blood administration, dobutamine, and metoprolol infusion. We compared the pACC values during IVRT and LVFP over the four different hemodynamic conditions with a peak rate of drop in LV pressure (-dP/dt(min)) and the time constant of LV isovolumic pressure decay (tau), as measured with a high-frequency manometer-tipped catheter. RESULTS: The pACC of the septal side of the mitral valve annulus during IVRT showed a good correlation with -dP/dt(min) (r = -0.80, p < 0.0001) and tau (r = -0.87, p < 0.0001). The mean left atrial pressure (LAP) correlated well with the septal side pACC during LVFP (r = 0.81, p < 0.0001). There was a weak correlation between the mitral valve annulus pACC at the LV lateral wall and mean LAP. CONCLUSIONS: The pACC during IVRT is a sensitive, preload-independent marker for evaluation of LV diastolic function. In addition, pACC during LVFP correlated well with mean LAP.

Bilateral Lung Transplantation From a Donor With Heparin-Induced Thrombocytopenia.

We report the case of a 46-year-old male patient with a history of cystic fibrosis who received bilateral lung transplantation from a donor who died secondary to complications of heparin-induced thrombocytopenia. Postoperatively, he exhibited transient focal neurologic deficits and radiographic evidence of multiple cortical and subcortical infarctions. He was treated with a combination of fondaparinux and standard immunosuppressive therapy, made a full recovery, and experienced significantly improved lung function compared to pretransplantation capacity.

Strain rate acceleration yields a better index for evaluating left ventricular contractile function as compared with tissue velocity acceleration during isovolumic contraction time: an in vivo study.

OBJECTIVE: Our study aimed to investigate whether strain rate acceleration (SRA) during isovolumic contraction time (IVCT) could serve as a sensitive indicator of myocardial function. METHODS: A total of 8 sheep underwent occlusion of left anterior descending coronary artery or diagonal branches and 2 sheep underwent left circumflex coronary artery occlusion to create septal, apical, or basal segment myocardial ischemia 19 to 27 weeks before the study. Baseline, volume-loading, dobutamine, and metoprolol infusion were used to produce 4 hemodynamic stages for each sheep. Doppler tissue imaging was acquired using a 5-MHz probe (GE/VingMed Vivid Five, GE Medical Systems, Milwaukee, Wis) on open-chest animals using the liver as a standoff at the apex. Using software (EchoPac, GE Medical Systems), SRA during IVCT was calculated and compared with tissue velocity acceleration (TVA) during IVCT from areas located in the normal and ischemic zones. Also, invasively monitored left ventricle dP/dt was measured as reference contractile function. RESULTS: Both TVA and SRA during IVCT showed higher values for normal tissue than for ischemic area (P <.0001). SRA for normal wall segments changed significantly during the 4 stages (P =.01) with corresponding changes on high-fidelity left ventricular pressure catheters (r = 0.92). TVA over normal segments showed no significant change (P =.29) in the 4 hemodynamic stages. Both TVA and SRA of the ischemic segments showed no significant change with pharmacologic maneuvers or loading conditions. CONCLUSIONS: SRA and TVA during IVCT are both useful indicators for detecting abnormal heart wall motion. However, SRA tends to be more sensitive than TVA for differentiating the response to stress conditions.

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.

Vagal nerve stimulation reduces anterior mitral valve leaflet stiffness in the beating ovine heart.

AIM: The functional significance of the autonomic nerves in the anterior mitral valve leaflet (AML) is unknown. We tested the hypothesis that remote stimulation of the vagus nerve (VNS) reduces AML stiffness in the beating heart. METHODS: Forty-eight radiopaque-markers were implanted into eleven ovine hearts to delineate left ventricular and mitral anatomy, including an AML array. The anesthetized animals were then taken to the catheterization laboratory and 4-D marker coordinates obtained from biplane videofluoroscopy before and after VNS. Circumferential (E(circ)) and radial (E(rad)) stiffness values for three separate AML regions, Annulus, Belly and Edge, were obtained from inverse finite element analysis of AML displacements in response to trans-leaflet pressure changes during isovolumic contraction (IVC) and isovolumic relaxation (IVR). RESULTS: VNS reduced heart rate: 94±9 vs. 82±10min(-1), (mean±SD, p<0.001). Circumferential AML stiffness was significantly reduced in all three regions during IVC and IVR (all p<0.05). Radial AML stiffness was reduced from control in the annular and belly regions at both IVC and IVR (P<0.05), while the reduction did not reach significance at the AML edge. CONCLUSION: These observations suggest that one potential functional role for the parasympathetic nerves in the AML is to alter leaflet stiffness. Neural control of the contractile tissue in the AML could be part of a central control system capable of altering valve stiffness to adapt to changing hemodynamic demands.