Age-related enhanced degeneration of bioprosthetic valves due to leaflet calcification, tissue crosslinking, and structural changes.

AIMS: Bioprosthetic heart valves (BHVs), made from glutaraldehyde-fixed heterograft materials, are subject to more rapid structural valve degeneration (SVD) in paediatric and young adult patients. Differences in blood biochemistries and propensity for disease accelerate SVD in these patients, which results in multiple re-operations with compounding risks. The goal of this study is to investigate the mechanisms of BHV biomaterial degeneration and present models for studying SVD in young patients and juvenile animal models. METHODS AND RESULTS: We studied SVD in clinical BHV explants from paediatric and young adult patients, juvenile sheep implantation model, rat subcutaneous implants, and an ex vivo serum incubation model. BHV biomaterials were analysed for calcification, collagen microstructure (alignment and crimp), and crosslinking density. Serum markers of calcification and tissue crosslinking were compared between young and adult subjects. We demonstrated that immature subjects were more susceptible to calcification, microstructural changes, and advanced glycation end products formation. In vivo and ex vivo studies comparing immature and mature subjects mirrored SVD in clinical observations. The interaction between host serum and BHV biomaterials leads to significant structural and biochemical changes which impact their functions. CONCLUSIONS: There is an increased risk for accelerated SVD in younger subjects, both experimental animals and patients. Increased calcification, altered collagen microstructure with loss of alignment and increased crimp periods, and increased crosslinking are three main characteristics in BHV explants from young subjects leading to SVD. Together, our studies establish a basis for assessing the increased susceptibility of BHV biomaterials to accelerated SVD in young patients.

In vivo assessment of mitral valve leaflet remodelling following myocardial infarction.

Each year, more than 40,000 people undergo mitral valve (MV) repair surgery domestically to treat regurgitation caused by myocardial infarction (MI). Although continual MV tissue remodelling following repair is believed to be a major contributor to regurgitation recurrence, the effects of the post-MI state on MV remodelling remain poorly understood. This lack of understanding limits our ability to predict the remodelling of the MV both post-MI and post-surgery to facilitate surgical planning. As a necessary first step, the present study was undertaken to noninvasively quantify the effects of MI on MV remodelling in terms of leaflet geometry and deformation. MI was induced in eight adult Dorset sheep, and real-time three-dimensional echocardiographic (rt-3DE) scans were collected pre-MI as well as at 0, 4, and 8 weeks post-MI. A previously validated image-based morphing pipeline was used to register corresponding open- and closed-state scans and extract local in-plane strains throughout the leaflet surface at systole. We determined that MI induced permanent changes in leaflet dimensions in the diastolic configuration, which increased with time to 4 weeks, then stabilised. MI substantially affected the systolic shape of the MV, and the range of stretch experienced by the MV leaflet at peak systole was substantially reduced when referred to the current time-point. Interestingly, when we referred the leaflet strains to the pre-MI configuration, the systolic strains remained very similar throughout the post-MI period. Overall, we observed that post-MI ventricular remodeling induced permanent changes in the MV leaflet shape. This predominantly affected the MV's diastolic configuration, leading in turn to a significant decrease in the range of stretch experienced by the leaflet when referenced to the current diastolic configuration. These findings are consistent with our previous work that demonstrated increased plastic (i.e. non-recoverable) leaflet deformations post-MI, that was completely accounted for by the associated changes in collagen fiber structure. Moreover, we demonstrated through noninvasive methods that the state of the MV leaflet can elucidate the progression and extent of MV adaptation following MI and is thus highly relevant to the design of current and novel patient specific minimally invasive surgical repair strategies.

Left atrial geometry in an ovine ischemic mitral regurgitation model: implications for transcatheter mitral valve replacement devices with a left atrial anchoring mechanism.

BACKGROUND: Transcatheter mitral valve replacement (TMVR) is a challenging, but promising minimally invasive treatment option for patients with mitral valve disease. Depending on the anchoring mechanism, complications such as mitral leaflet or chordal disruption, aortic valve disruption or left ventricular outflow tract obstruction may occur. Supra-annular devices only anchor at the left atrial (LA) level with a low risk of these complications. For development of transcatheter valves based on LA anchoring, animal feasibility studies are required. In this study we sought to describe LA systolic and diastolic geometry in an ovine ischemic mitral regurgitation (IMR) model using magnetic resonance imaging (MRI) and echocardiography in order to facilitate future research focusing on TMVR device development for (I)MR with LA anchoring mechanisms. METHODS: A group of 10 adult male Dorsett sheep underwent a left lateral thoracotomy. Posterolateral myocardial infarction was created by ligation of the left circumflex coronary artery, the obtuse marginal and diagonal branches. MRI and echocardiography were performed at baseline and 8 weeks after myocardial infarction (MI). RESULTS: Six animals survived to 8 weeks follow-up. All animals had grade 2 + or higher IMR 8 weeks post-MI. All LA geometric parameters did not change significantly 8 weeks post-MI compared to baseline. Diastolic and systolic interpapillary muscle distance increased significantly 8 weeks post-MI. CONCLUSIONS: Systolic and diastolic LA geometry do not change significantly in the presence of grade 2 + or higher IMR 8 weeks post-MI. These findings help facilitate future tailored TMVR device development with LA anchoring mechanisms.

Dynamic Volumetric Assessment of the Aortic Root: The Influence of Bicuspid Aortic Valve Competence.

BACKGROUND: Aortic root evaluation is conventionally based on 2-dimensional measurements at a single phase of the cardiac cycle. This work presents an image analysis method for assessing dynamic 3-dimensional changes in the aortic root of minimally calcified bicuspid aortic valves (BAVs) with and without moderate to severe aortic regurgitation. METHODS: The aortic root was segmented over the full cardiac cycle in 3-dimensional transesophageal echocardiographic images acquired from 19 patients with minimally calcified BAVs and from 16 patients with physiologically normal tricuspid aortic valves (TAVs). The size and dynamics of the aortic root were assessed using the following image-derived measurements: absolute mean root volume and mean area at the level of the ventriculoaortic junction, sinuses of Valsalva, and sinotubular junction, as well as normalized root volume change and normalized area change of the ventriculoaortic junction, sinuses of Valsalva, and sinotubular junction over the cardiac cycle. RESULTS: Normalized volume change over the cardiac cycle was significantly greater in BAV roots with moderate to severe regurgitation than in normal TAV roots and in BAV roots with no or mild regurgitation. Aortic root dynamics were most significantly different at the mid-level of the sinuses of Valsalva in BAVs with moderate to severe regurgitation than in competent TAVs and BAVs. CONCLUSIONS: Echocardiographic reconstruction of the aortic root demonstrates significant differences in dynamics of BAV roots with moderate to severe regurgitation relative to physiologically normal TAVs and competent BAVs. This finding may have implications for risk of future dilatation, dissection, or rupture, which warrant further investigation.

Intraoperative post-annuloplasty three-dimensional valve analysis does not predict recurrent ischemic mitral regurgitation.

BACKGROUND: High ischemic mitral regurgitation (IMR) recurrence rates continue to plague IMR repair with undersized ring annuloplasty. We have previously shown that pre-repair three-dimensional echocardiography (3DE) analysis is highly predictive of IMR recurrence. The objective of this study was to determine the quantitative change in 3DE annular and leaflet tethering parameters immediately after repair and to determine if intraoperative post-repair 3DE parameters would be able to predict IMR recurrence 6 months after repair. METHODS: Intraoperative pre- and post-repair transesophageal real-time 3DE was performed in 35 patients undergoing undersized ring annuloplasty for IMR. An advanced modeling algorhythm was used to assess 3D annular geometry and regional leaflet tethering. IMR recurrence (≥ grade 2) was assessed with transthoracic echocardiography 6 months after repair. RESULTS: Annuloplasty significantly reduced septolateral diameter, commissural width, annular area, and tethering volume and significantly increased all segmental tethering angles (except A2). Intraoperative post-repair annular geometry and leaflet tethering did not differ significantly between patients with recurrent IMR (n = 9) and patients with non-recurrent IMR (n = 26). No intraoperative post-repair predictors of IMR recurrence could be identified. CONCLUSIONS: Undersized ring annuloplasty changes mitral geometry acutely, exacerbates leaflet tethering, and generally fixes IMR acutely, but it does not always fix the delicate underlying chronic problem of continued left ventricular dilatation and remodeling. This may explain why pre-repair 3D valve geometry (which reflects chronic left ventricular remodeling) is highly predictive of recurrent IMR, whereas immediate post-repair 3D valve geometry (which does not completely reflect chronic left ventricular remodeling anymore) is not.

Iron imaging in myocardial infarction reperfusion injury.

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.

Optimized mitral annuloplasty ring design reduces loading in the posterior annulus.

OBJECTIVE: The study objective was to develop a novel annuloplasty ring with regional flexibility and assess its suture force dynamics in healthy ovine subjects compared with fully rigid or fully flexible rings. METHODS: Materially heterogeneous rings were created with rigid anterior and posterior, and flexible commissural segments. These rings were created to match the geometry of the Profile 3D ring (Medtronic, Minneapolis, Minn). Each ring was instrumented with 10 force transducers to measure cyclic suture forces (FC) and undersized annuloplasty was performed in 6 healthy ovine subjects. Each FC was recorded and examined for cardiac cycles reaching a maximum left ventricular pressure of 100, 125, and 150 mm Hg. FC was compared with previously reported values from fully rigid Profile 3D and fully flexible prototype rings. RESULTS: Relative to the fully rigid ring, the heterogeneous ring exhibited 48% reduction in FC at its commissural (rigid vs heterogeneous: 1.80 ± 0.94 N vs 0.95 ± 0.52 N; P < .001) and 32% reduction in posterior (1.90 ± 0.92 N vs 1.29 ± 0.91 N; P < .001) regions, but not in its anterior region (2.45 ± 1.21 N vs 2.23 ± 1.22 N; P = .279). Relative to the fully flexible ring, the heterogeneous ring exhibited no significant differences in FC in any region. CONCLUSIONS: The reduced FC of the heterogeneous ring relative to the fully rigid ring suggests a promising approach to reduce suture loading while preserving the annular remodeling capability of fully rigid rings. Future studies in diseased subjects are necessary to explore repair effectiveness of this ring.

Quantitative three-dimensional echocardiographic analysis of the bicuspid aortic valve and aortic root: A single modality approach.

BACKGROUND: Patients with bicuspid aortic valves (BAV) are heterogeneous with regard to patterns of root remodeling and valvular dysfunction. Two-dimensional echocardiography is the standard surveillance modality for patients with aortic valve dysfunction. However, ancillary computed tomography or magnetic resonance imaging is often necessary to characterize associated patterns of aortic root pathology. Conversely, the pairing of three-dimensional (3D) echocardiography with novel quantitative modeling techniques allows for a single modality description of the entire root complex. We sought to determine 3D aortic valve and root geometry with this quantitative approach. METHODS: Transesophageal real-time 3D echocardiography was performed in five patients with tricuspid aortic valves (TAV) and in five patients with BAV. No patient had evidence of valvular dysfunction or aortic root pathology. A customized image analysis protocol was used to assess 3D aortic annular, valvular, and root geometry. RESULTS: Annular, sinus and sinotubular junction diameters and areas were similar in both groups. Coaptation length and area were higher in the TAV group (7.25 ± 0.98 mm and 298 ± 118 mm2 , respectively) compared to the BAV group (5.67 ± 1.33 mm and 177 ± 43 mm2 ; P = .07 and P = .01). Cusp surface area to annular area, coaptation height, and the sub- and supravalvular tenting indices did not differ significantly between groups. CONCLUSIONS: Single modality 3D echocardiography-based modeling allows for a quantitative description of the aortic valve and root geometry. This technique together with novel indices will improve our understanding of normal and pathologic geometry in the BAV population and may help to identify geometric predictors of adverse remodeling and guide tailored surgical therapy.

Injectable Shear-Thinning Hydrogels Prevent Ischemic Mitral Regurgitation and Normalize Ventricular Flow Dynamics.

Injectable hydrogels are known to attenuate left-ventricular (LV) remodeling following myocardial infarction (MI), dependent on material mechanical properties. The effect of hydrogel injection on ischemic mitral regurgitation (IMR) resultant from LV remodeling remains relatively unexplored. This study uses multiple imaging methods to evaluate the efficacy of injectable hydrogels with tunable modulus to prevent post-MI development of IMR. Posterolateral MI was induced in 20 sheep with subsequent epicardial injection of saline (control (MI); n = 7), soft hydrogel (guest-host crosslinking, modulus <1 kPa, n = 7), or stiff hydrogel (dual-crosslinking, modulus = 41.4 ± 4.3 kPa, n = 6) within the infarct region and 8-week follow-up. IMR and valve geometry were assessed by echocardiography. LV geometry (long-axis dimension, posterior chordae length) and ventricular flow dynamics were assessed by magnetic resonance imaging. IMR developed in MI controls at 8 weeks and was attenuated with hydrogel treatment (IMR grade for MI: 1.86 ± 0.69; guest-host crosslinking: 1.29 ± 1.11; dual-crosslinking: 0.50 ± 0.55, P = 0.02 vs MI). Tethering of the posterior leaflet increased in MI controls, but not with stiff hydrogel treatment. Across cohorts, IMR was correlated with changes in the long-axis dimension (Spearman R = 0.77) and posterior chordae length (Spearman R = 0.64). Intraventricular flow dynamics were highly disturbed in MI controls, but stiff hydrogel treatment normalized flow patterns and reduced the prevalence of large (≥2+ MR, >5 mL) regurgitant volumes. Injectable hydrogels attenuated subvalvular remodeling and leaflet tethering, preventing IMR development and normalizing LV flow dynamics. Hydrogels with a supraphysiological modulus yielded best outcomes.

Differential Expression of Transforming Growth Factor-ß1 Is Associated With Fetal Regeneration After Myocardial Infarction.

BACKGROUND: Global extracellular matrix (ECM)-related gene expression is decreased after myocardial infarction (MI) in fetal sheep when compared with adult sheep. Transforming growth factor (TGF)-ß1 is a key regulator of ECM; therefore we hypothesize that TGF-ß1 is differentially expressed in adult and fetal infarcts after MI. METHODS: Adult and fetal sheep underwent MI via ligation of the left anterior descending coronary artery. Expression of TGF-ß1 and ECM-related genes was evaluated by ovine-specific microarray and quantitative polymerase chain reaction. Fibroblasts from the left ventricle of adult and fetal hearts were treated with TGF-ß1 or a TGF-ß1 receptor inhibitor (LY36497) to evaluate the effect of TGF-ß1 on ECM-related genes. RESULTS: Col1a1, col3a1, and MMP9 expression were increased in adult infarcts 3 and 30 days after MI but were upregulated in fetal infarcts only 3 days after MI. Three days after MI elastin expression was increased in adult infarcts. Despite upregulation in adult infarcts both 3 and 30 days after MI, TGF-ß1 was not upregulated in fetal infarcts at any time point. Inhibition of the TGF-ß1 receptor in adult cardiac fibroblasts decreased expression of col1a1, col3a1, MMP9, elastin, and TIMP1, whereas treatment of fetal cardiac fibroblasts with TGF-ß1 increased expression of these genes. CONCLUSIONS: TGF-ß1 is increased in adult infarcts compared with regenerative, fetal infarcts after MI. Although treatment of fetal cardiac fibroblasts with TGF-ß1 conveys an adult phenotype, inhibition of TGF-ß1 conveys a fetal phenotype to adult cardiac fibroblasts. Decreasing TGF-ß1 after MI may facilitate myocardial regeneration by "fetalizing" the otherwise fibrotic, adult response to MI.

Mitral annuloplasty ring suture forces: Impact of surgeon, ring, and use conditions.

OBJECTIVE: The study objective was to quantify the effect of ring type, ring-annulus sizing, suture position, and surgeon on the forces required to tie down and constrain a mitral annuloplasty ring to a beating heart. METHODS: Physio (Edwards Lifesciences, Irvine, Calif) or Profile 3D (Medtronic, Dublin, Ireland) annuloplasty rings were instrumented with suture force transducers and implanted in ovine subjects (N = 23). Tie-down forces and cyclic contractile forces were recorded and analyzed at 10 suture positions and at 3 levels of increasing peak left ventricular pressure. RESULTS: Across all conditions, tie-down force was 2.7 ± 1.4 N and cyclic contractile force was 2.0 ± 1.2 N. Tie-down force was not meaningfully affected by any factor except surgeon. Significant differences in overall and individual tie-down forces were observed between the 2 primary implanting surgeons. No other factors were observed to significantly affect tie-down force. Contractile suture forces were significantly reduced by ring-annulus true sizing. This was driven almost exclusively by Physio cases and by reduction along the anterior aspect, where dehiscence is less common clinically. Contractile suture forces did not differ significantly between ring types. However, when undersizing, Profile 3D forces were significantly more uniform around the annular circumference. A suture's tie-down force did not correlate to its eventual contractile force. CONCLUSIONS: Mitral annuloplasty suture loading is influenced by ring type, ring-annulus sizing, suture position, and surgeon, suggesting that reports of dehiscence may not be merely a series of isolated errors. When compared with forces known to cause suture dehiscence, these in vivo suture loading data aid in establishing potential targets for reducing the occurrence of ring dehiscence.

Cardiac Progenitor Cell Recruitment Drives Fetal Cardiac Regeneration by Enhanced Angiogenesis.

BACKGROUND: In contrast to adults, the fetal response to myocardial infarction (MI) is regenerative, requiring the recruitment of cardiac progenitor cells to replace infarcted myocardium. Macrophage contribution to tissue repair depends on their phenotype: M1 are proinflammatory and initiate angiogenesis; M2a are profibrotic and contribute to blood vessels maturation; and M2c are proremodeling and proangiogenesis. The goal of the present study was to expand on this work by examining cardiac progenitor cells recruitment, and the role of macrophages in promoting angiogenesis and cardiac regeneration in the fetal heart after MI. METHODS: Fetal and adult sheep underwent MI and were sacrificed 3 or 30 days after MI. Some fetal hearts received stromal cell-derived factor-1α-inhibitor treatment. The microvasculature was evaluated by micro-computed tomography, gene expression was evaluated by real-time polymerase chain reaction, and vessels counts were evaluated by immunohistochemistry. RESULTS: Micro-computed tomography analysis showed restoration of microvasculature in fetal hearts after MI. Vascular endothelial growth factor-α increased, and the expression of tissue markers associated with the M1, M2a, and M2c macrophage phenotypes were elevated at day 3 after MI, but returned to baseline by 30 days after MI. In contrast, adult hearts after MI exhibited low vascular endothelial growth factor-α and persistent upregulation of all macrophage markers, consistent with prolonged inflammation, fibrosis, and remodeling. Inhibition of stromal cell-derived factor-1α in fetal infarcts prevented angiogenesis, decreased vascular endothelial growth factor-α, and was associated with a sustained increase in M1, M2a, and M2c markers after MI. CONCLUSIONS: Changes in angiogenesis and macrophage phenotype-related gene expression after MI are important for the fetal regenerative response to MI and are mediated at least in part by cardiac progenitor cells recruitment.

On the in vivo function of the mitral heart valve leaflet: insights into tissue-interstitial cell biomechanical coupling.

There continues to be a critical need for developing data-informed computational modeling techniques that enable systematic evaluations of mitral valve (MV) function. This is important for a better understanding of MV organ-level biomechanical performance, in vivo functional tissue stresses, and the biosynthetic responses of MV interstitial cells (MVICs) in the normal, pathophysiological, and surgically repaired states. In the present study, we utilized extant ovine MV population-averaged 3D fiducial marker data to quantify the MV anterior leaflet (MVAL) deformations in various kinematic states. This approach allowed us to make the critical connection between the in vivo functional and the in vitro experimental configurations. Moreover, we incorporated the in vivo MVAL deformations and pre-strains into an enhanced inverse finite element modeling framework (Path 1) to estimate the resulting in vivo tissue prestresses [Formula: see text] and the in vivo peak functional tissue stresses [Formula: see text]. These in vivo stress estimates were then cross-verified with the results obtained from an alternative forward modeling method (Path 2), by taking account of the changes in the in vitro and in vivo reference configurations. Moreover, by integrating the tissue-level kinematic results into a downscale MVIC microenvironment FE model, we were able to estimate, for the first time, the in vivo layer-specific MVIC deformations and deformation rates of the normal and surgically repaired MVALs. From these simulations, we determined that the placement of annuloplasty ring greatly reduces the peak MVIC deformation levels in a layer-specific manner. This suggests that the associated reductions in MVIC deformation may down-regulate MV extracellular matrix maintenance, ultimately leading to reduction in tissue mechanical integrity. These simulations provide valuable insight into MV cellular mechanobiology in response to organ- and tissue-level alternations induced by MV disease or surgical repair. They will also assist in the future development of computer simulation tools for guiding MV surgery procedure with enhanced durability and improved long-term surgical outcomes.

Regional Heterogeneity in the Mitral Valve Apparatus in Patients With Ischemic Mitral Regurgitation.

BACKGROUND: Apical displacement of the coaptation point of the mitral valve (MV) in response to ischemic mitral regurgitation (IMR) represents remodeling of the MV apparatus. Whereas it implies chronicity, it lacks specificity in discriminating normal from a significantly remodeled MV apparatus. Regional aspects of MV remodeling have shown superior value over global remodeling in predicting recurrence after MV repair for IMR. Quite possibly, presence of specific regional changes in MV geometry that are unique to chronic IMR patients could also be used to diagnose the presence and track progression of remodeling. Knowledge of these changes in MV apparatus in patients with IMR can possibly be used to identify patients for surgical intervention before irreversible remodeling occurs. METHODS: Three-dimensional transesophageal echocardiographic data were collected from patients who underwent MV surgery for IMR (IMR group, n = 66), and from patients with normal valvular and biventricular function (control group, n = 10). The acquired data of the MV were geometrically analyzed to make regional comparisons between the IMR and the control group to identify measurements that reliably differentiate normal from remodeled MVs. RESULTS: Lengthening of the middle potion of the anterior annulus (A2 regional perimeter: 11.149 mm versus 9.798 mm, p = 0.0041), larger nonplanarity angle (147.985 versus 140.720 degrees, p = 0.0459), and increased tenting angle of the posteromedial scallop of the posterior leaflet (P3 tenting angle: 44.354 versus 40.461 degrees, p = 0.0435) were sufficient in differentiating between IMR and the control group. CONCLUSIONS: Specific three-dimensional changes in MV geometry can be used to reliably identify a significantly remodeled valve apparatus.

Assessment of myocardial injury after reperfused infarction by T1ρ cardiovascular magnetic resonance.

BACKGROUND: The evolution of T1ρ and of other endogenous contrast methods (T2, T1) in the first month after reperfused myocardial infarction (MI) is uncertain. We conducted a study of reperfused MI in pigs to serially monitor T1ρ, T2 and T1 relaxation, scar size and transmurality at 1 and 4 weeks post-MI. METHODS: Ten Yorkshire swine underwent 90 min of occlusion of the circumflex artery and reperfusion. T1ρ, T2 and native T1 maps and late gadolinium enhanced (LGE) cardiovascular magnetic resonance (CMR) data were collected at 1 week (n = 10) and 4 weeks (n = 5). Semi-automatic FWHM (full width half maximum) thresholding was used to assess scar size and transmurality and compared to histology. Relaxation times and contrast-to-noise ratio were compared in healthy and remote myocardium at 1 and 4 weeks. Linear regression and Bland-Altman was performed to compare infarct size and transmurality. RESULTS: Relaxation time differences between infarcted and remote myocardial tissue were ∆T1 (infarct-remote) = 421.3 ± 108.8 (1 week) and 480.0 ± 33.2 ms (4 week), ∆T1ρ = 68.1 ± 11.6 and 74.3 ± 14.2, and ∆T2 = 51.0 ± 10.1 and 59.2 ± 11.4 ms. Contrast-to-noise ratio was CNRT1 = 7.0 ± 3.5 (1 week) and 6.9 ± 2.4 (4 week), CNRT1ρ = 12.0 ± 6.2 and 12.3 ± 3.2, and CNRT2 = 8.0 ± 3.6 and 10.3 ± 5.8. Infarct size was not significantly different for T1ρ, T1 and T2 compared to LGE (p = 0.14) and significantly decreased from 1 to 4 weeks (p < 0.01). Individual infarct size changes were ∆T1ρ = -3.8%, ∆T1 = -3.5% and ∆LGE = -2.8% from 1 - 4 weeks, but there was no observed change in infarct size for T2 or histologically. CONCLUSIONS: T1ρ was highly correlated with alterations left ventricle (LV) pathology at 1 and 4 weeks post-MI and therefore it may be a useful method endogenous contrast imaging of infarction.

Injectable Shear-Thinning Hydrogels for Minimally Invasive Delivery to Infarcted Myocardium to Limit Left Ventricular Remodeling.

BACKGROUND: Injectable, acellular biomaterials hold promise to limit left ventricular remodeling and heart failure precipitated by infarction through bulking or stiffening the infarct region. A material with tunable properties (eg, mechanics, degradation) that can be delivered percutaneously has not yet been demonstrated. Catheter-deliverable soft hydrogels with in vivo stiffening to enhance therapeutic efficacy achieve these requirements. METHODS AND RESULTS: We developed a hyaluronic acid hydrogel that uses a tandem crosslinking approach, where the first crosslinking (guest-host) enabled injection and localized retention of a soft (<1 kPa) hydrogel. A second crosslinking reaction (dual-crosslinking) stiffened the hydrogel (41.4±4.3 kPa) after injection. Posterolateral infarcts were investigated in an ovine model (n≥6 per group), with injection of saline (myocardial infarction control), guest-host hydrogels, or dual-crosslinking hydrogels. Computational (day 1), histological (1 day, 8 weeks), morphological, and functional (0, 2, and 8 weeks) outcomes were evaluated. Finite-element modeling projected myofiber stress reduction (>50%; P<0.001) with dual-crosslinking but not guest-host injection. Remodeling, assessed by infarct thickness and left ventricular volume, was mitigated by hydrogel treatment. Ejection fraction was improved, relative to myocardial infarction at 8 weeks, with dual-crosslinking (37% improvement; P=0.014) and guest-host (15% improvement; P=0.058) treatments. Percutaneous delivery via endocardial injection was investigated with fluoroscopic and echocardiographic guidance, with delivery visualized by magnetic resonance imaging. CONCLUSIONS: A percutaneous delivered hydrogel system was developed, and hydrogels with increased stiffness were found to be most effective in ameliorating left ventricular remodeling and preserving function. Ultimately, engineered systems such as these have the potential to provide effective clinical options to limit remodeling in patients after infarction.

Modeling the Myxomatous Mitral Valve With Three-Dimensional Echocardiography.

BACKGROUND: Degenerative mitral valve disease is associated with variable and complex defects in valve morphology. Three-dimensional echocardiography (3DE) has shown promise in aiding preoperative planning for patients with this disease but to date has not been as transformative as initially predicted. The clinical usefulness of 3DE has been limited by the laborious methods currently required to extract quantitative data from the images. METHODS: To maximize the utility of 3DE for preoperative valve evaluation, this work describes an automated 3DE image analysis method for generating models of the mitral valve that are well suited for both qualitative and quantitative assessment. The method is unique in that it captures detailed alterations in mitral leaflet and annular morphology and produces image-derived models with locally varying leaflet thickness. The method is evaluated on midsystolic transesophageal 3DE images acquired from 22 subjects with myxomatous degeneration and from 22 subjects with normal mitral valve morphology. RESULTS: Relative to manual image analysis, the automated method accurately represents both normal and complex leaflet geometries with a mean boundary displacement error on the order of one image voxel. A detailed quantitative analysis of the valves is presented and reveals statistically significant differences between normal and myxomatous valves with respect to numerous aspects of annular and leaflet geometry. CONCLUSIONS: This work demonstrates a successful methodology for the relatively rapid quantitative description of the complex mitral valve distortions associated with myxomatous degeneration. The methodology has the potential to significantly improve surgical planning for patients with complex mitral valve disease.