Simulated Effects of Acute Left Ventricular Myocardial Infarction On Mitral Regurgitation in an Ovine Model.

Development of patient specific models of LV-MV interactions in ischemic mitral regurgitation (IMR) are complicated by the substantial variability and complex etiologies, making it difficult to extract underlying mechanisms. We thus developed a detailed ovine LV-MV finite element model based for the normal and acute post-MI states. The ovine LV FEM model was first extended to incorporate a detailed MV leaflet sub-model with a functionally-equivalent CT structure. The resulting complete LV-MV model was first used to simulate the full cardiac cycle in the normal state to establish baseline responses. We then simulated regional acute infarctions of varying sizes in various known infarct anatomical locations by shutting down the local myocardial contractility, while remote regions were allowed to adjust their active contractile patterns to maintain the prescribed pressure-volume loop. Simulation results indicated that the posterobasal infarct induced the largest MV regurgitation orifice area, consistent with experimental observations. We incorporated previously reported MV leaflet pre-strains (Amini et al., Ann Biomed Eng. 2012 Jul;40(7):1455-67) in the simulations, which then resulted in excellent agreement. Extensional deformations of the posterior leaflets occurred in the posterobasal and laterobasal infarcts, while compressive deformations of anterior leaflets were observed in the anterobasal infarct. The present study is the first detailed LV-MV simulations to reveal the important role of ,V EAF;ET pre-strain For accurate model prediction, underscoring that proper accounting of residual strains is an essential part of accurate simulations of organ level function.

Patient-Specific Quantitative In-Vivo Assessment of Human Mitral Valve Leaflet Strain Before and After MitraClip Repair.

PURPOSE: Mitral regurgitation (MR) is a highly prevalent and deadly cardiac disease characterized by improper mitral valve (MV) leaflet coaptation. Among the plethora of available treatment strategies, the MitraClip is an especially safe option, but optimizing its long-term efficacy remains an urgent challenge. METHODS: We applied our noninvasive image-based strain computation pipeline [1] to intraoperative transesophageal echocardiography datasets taken from ten patients undergoing MitraClip repair, spanning a range of MR etiologies and MitraClip configurations. We then analyzed MV leaflet strains before and after MitraClip implementation to develop a better understanding of (1) the pre-operative state of human regurgitant MV, and (2) the MitraClip's impact on the MV leaflet deformations. RESULTS: The MV pre-operative strain fields were highly variable, underscoring both the heterogeneity of the MR in the patient population and the need for patient-specific treatment approaches. Similarly, there were no consistent overall post-operative strain patterns, although the average A2 segment radial strain difference between pre- and post-operative states was consistently positive. In contrast, the post-operative strain fields were better correlated to their respective pre-operative strain fields than to the inter-patient post-operative strain fields. This quantitative result implies that the patient specific pre-operative state of the MV guides its post-operative deformation, which suggests that the post-operative state can be predicted using pre-operative data-derived modelling alone. CONCLUSIONS: The pre-operative MV leaflet strain patterns varied considerably across the range of MR disease states and after MitraClip repair. Despite large inter-patient heterogeneity, the post-operative deformation appears principally dictated by the pre-operative deformation state. This novel finding suggests that though the variation in MR functional state and MitraClip-induced deformation were substantial, the post-operative state can be predicted from the pre-operative data alone. This study suggests that, with use of larger patient cohort and corresponding long-term outcomes, quantitative predictive factors of MitraClip durability can be identified.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

A Computational Pipeline for Patient-Specific Prediction of the Postoperative Mitral Valve Functional State.

While mitral valve (MV) repair remains the preferred clinical option for mitral regurgitation (MR) treatment, long-term outcomes remain suboptimal and difficult to predict. Furthermore, pre-operative optimization is complicated by the heterogeneity of MR presentations and the multiplicity of potential repair configurations. In the present work, we established a patient-specific MV computational pipeline based strictly on standard-of-care pre-operative imaging data to quantitatively predict the post-repair MV functional state. First, we established human mitral valve chordae tendinae (MVCT) geometric characteristics obtained from five CT-imaged excised human hearts. From these data, we developed a finite-element model of the full patient-specific MV apparatus that included MVCT papillary muscle origins obtained from both the in vitro study and the pre-operative three-dimensional echocardiography images. To functionally tune the patient-specific MV mechanical behavior, we simulated pre-operative MV closure and iteratively updated the leaflet and MVCT prestrains to minimize the mismatch between the simulated and target end-systolic geometries. Using the resultant fully calibrated MV model, we simulated undersized ring annuloplasty (URA) by defining the annular geometry directly from the ring geometry. In three human cases, the postoperative geometries were predicted to 1 mm of the target, and the MV leaflet strain fields demonstrated close agreement with noninvasive strain estimation technique targets. Interestingly, our model predicted increased posterior leaflet tethering after URA in two recurrent patients, which is the likely driver of long-term MV repair failure. In summary, the present pipeline was able to predict postoperative outcomes from pre-operative clinical data alone. This approach can thus lay the foundation for optimal tailored surgical planning for more durable repair, as well as development of mitral valve digital twins.

Strain estimation in aortic roots from 4D echocardiographic images using medial modeling and deformable registration.

Even though the central role of mechanics in the cardiovascular system is widely recognized, estimating mechanical deformation and strains in-vivo remains an ongoing practical challenge. Herein, we present a semi-automated framework to estimate strains from four-dimensional (4D) echocardiographic images and apply it to the aortic roots of patients with normal trileaflet aortic valves (TAV) and congenital bicuspid aortic valves (BAV). The method is based on fully nonlinear shell-based kinematics, which divides the strains into in-plane (shear and dilatational) and out-of-plane components. The results indicate that, even for size-matched non-aneurysmal aortic roots, BAV patients experience larger regional shear strains in their aortic roots. This elevated strains might be a contributing factor to the higher risk of aneurysm development in BAV patients. The proposed framework is openly available and applicable to any tubular structures.

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.

Simulation of Mitral Valve Plasticity in Response to Myocardial Infarction.

Left ventricular myocardial infarction (MI) has broad and debilitating effects on cardiac function. In many cases, MI leads to ischemic mitral regurgitation (IMR), a condition characterized by incompetency of the mitral valve (MV). IMR has many deleterious effects as well as a high mortality rate. While various clinical treatments for IMR exist, success of these procedures remains limited, in large part because IMR dramatically alters the geometry and function of the MV in ways that are currently not well understood. Previous investigations of post-MI MV remodeling have elucidated that MV tissues have a significant ability to undergo a form of permanent inelastic deformations in the first phase of the post-MI period. These changes appear to be attributable to the altered loading and boundary conditions on the MV itself, as opposed to an independent pathophysiological process. Mechanistically, these results suggest that the MV mostly responds passively to MI during the first 8 weeks post-MI by undergoing a permanent deformation. In the present study, we developed the first computational model of this post-MI MV remodeling process, which we term "mitral valve plasticity." Integrating methodologies and insights from previous studies of in vivo ovine MV function, image-based patient-specific model development, and post-MI MV adaptation, we constructed a representative geometric model of a pre-MI MV. We then performed finite element simulations of the entire MV apparatus under time-dependent boundary conditions and accounting for changes to material properties equivalent to those observed 0-8 weeks post-MI. Our results suggest that during this initial period of adaptation, the MV response to MI can be accurately modeled using a soft tissue plasticity approach, similar to permanent set frameworks that have been applied previously in the context of exogenously crosslinked tissues.

Quantitative in vivo assessment of human mitral valve coaptation area after undersized ring annuloplasty repair for ischemic mitral regurgitation.

Objectives: Long-term outcomes of mitral valve repair procedures to correct ischemic mitral regurgitation remain unpredictable, due to an incomplete understanding of the disease process and the inability to reliably quantify the coaptation zone using echocardiography. Our objective was to quantify patient-specific mitral valve coaptation behavior from clinical echocardiographic images obtained before and after repair to assess coaptation restoration and its relationship with long-term repair durability. Methods: To circumvent the limitations of clinical imaging, we applied a simulation-based shape-matching technique that allowed high-fidelity reconstructions of the complete mitral valve in the systolic configuration. We then applied this method to an extant database of human regurgitant mitral valves before and after undersized ring annuloplasty to quantify the effect of the repair on mitral valve coaptation geometry. Results: Our method was able to successfully resolve the coaptation zone into distinct contacting and redundant regions. Results indicated that in patients whose regurgitation recurred 6 months postrepair, both the contacting and redundant regions were larger immediately postrepair compared with patients with no recurrence (P < .05), even when normalized to account for generally larger recurrent valves. Conclusions: Although increasing leaflet coaptation area is an intuitively obvious way to improve long-term repair durability, this study has implied that this may not be a reliable target for mitral valve repair. This study underscores the importance of a rigorous understanding of the consequences of repair techniques on mitral valve behavior, as well as a patient-specific approach to ischemic mitral regurgitation treatment within the context of mitral valve and left ventricle function.

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.

Fully Automated 3D Segmentation and Diffeomorphic Medial Modeling of the Left Ventricle Mitral Valve Complex in Ischemic Mitral Regurgitation.

There is an urgent unmet need to develop a fully-automated image-based left ventricle mitral valve analysis tool to support surgical decision making for ischemic mitral regurgitation patients. This requires an automated tool for segmentation and modeling of the left ventricle and mitral valve from immediate pre-operative 3D transesophageal echocardiography. Previous works have presented methods for semi-automatically segmenting and modeling the mitral valve, but do not include the left ventricle and do not avoid self-intersection of the mitral valve leaflets during shape modeling. In this study, we develop and validate a fully automated algorithm for segmentation and shape modeling of the left ventricular mitral valve complex from pre-operative 3D transesophageal echocardiography. We performed a 3-fold nested cross validation study on two datasets from separate institutions to evaluate automated segmentations generated by nnU-net with the expert manual segmentation which yielded average overall Dice scores of 0.82±0.03 (set A), 0.87±0.08 (set B) respectively. A deformable medial template was subsequently fitted to the segmentation to generate shape models. Comparison of shape models to the manual and automatically generated segmentations resulted in an average Dice score of 0.93-0.94 and 0.75-0.81 for the left ventricle and mitral valve, respectively. This is a substantial step towards automatically analyzing the left ventricle mitral valve complex in the operating room.

Stent-based delivery of AAV2 vectors encoding oxidation-resistant apoA1.

In-stent restenosis (ISR) complicates revascularization in the coronary and peripheral arteries. Apolipoprotein A1 (apoA1), the principal protein component of HDL possesses inherent anti-atherosclerotic and anti-restenotic properties. These beneficial traits are lost when wild type apoA1(WT) is subjected to oxidative modifications. We investigated whether local delivery of adeno-associated viral (AAV) vectors expressing oxidation-resistant apoA1(4WF) preserves apoA1 functionality. The efflux of 3H-cholesterol from macrophages to the media conditioned by endogenously produced apoA1(4WF) was 2.1-fold higher than for apoA1(WT) conditioned media in the presence of hypochlorous acid emulating conditions of oxidative stress. The proliferation of apoA1(WT)- and apoA1(4FW)-transduced rat aortic smooth muscle cells (SMC) was inhibited by 66% ± 10% and 65% ± 11%, respectively, in comparison with non-transduced SMC (p < 0.001). Conversely, the proliferation of apoA1(4FW)-transduced, but not apoA1(WT)-transduced rat blood outgrowth endothelial cells (BOEC) was increased 41% ± 5% (p < 0.001). Both apoA1 transduction conditions similarly inhibited basal and TNFα-induced reactive oxygen species in rat aortic endothelial cells (RAEC) and resulted in the reduced rat monocyte attachment to the TNFα-activated endothelium. AAV2-eGFP vectors immobilized reversibly on stainless steel mesh surfaces through the protein G/anti-AAV2 antibody coupling, efficiently transduced cells in culture modeling stent-based delivery. In vivo studies in normal pigs, deploying AAV2 gene delivery stents (GDS) preloaded with AAV2-eGFP in the coronary arteries demonstrated transduction of the stented arteries. However, implantation of GDS formulated with AAV2-apoA1(4WF) failed to prevent in-stent restenosis in the atherosclerotic vasculature of hypercholesterolemic diabetic pigs. It is concluded that stent delivery of AAV2-4WF while feasible, is not effective for mitigation of restenosis in the presence of severe atherosclerotic disease.

Patient-Specific Quantification of Normal and Bicuspid Aortic Valve Leaflet Deformations from Clinically Derived Images.

The clinical benefit of patient-specific modeling of heart valve disease remains an unrealized goal, often a result of our limited understanding of the in vivo milieu. This is particularly true in assessing bicuspid aortic valve (BAV) disease, the most common cardiac congenital defect in humans, which leads to premature and severe aortic stenosis or insufficiency (AS/AI). However, assessment of BAV risk for AS/AI on a patient-specific basis is hampered by the substantial degree of anatomic and functional variations that remain largely unknown. The present study was undertaken to utilize a noninvasive computational pipeline ( https://doi.org/10.1002/cnm.3142 ) that directly yields local heart valve leaflet deformation information using patient-specific real-time three-dimensional echocardiographic imaging (rt-3DE) data. Imaging data was collected for patients with normal tricuspid aortic valve (TAV, [Formula: see text]) and those with BAV ([Formula: see text] with fused left and right coronary leaflets and [Formula: see text] with fused right and non-coronary leaflets), from which the medial surface of each leaflet was extracted. The resulting deformation analysis resulted in, for the first time, quantified differences between the in vivo functional deformations of the TAV and BAV leaflets. Our approach was able to capture the complex, heterogeneous surface deformation fields in both TAV and BAV leaflets. We were able to identify and quantify differences in stretch patterns between leaflet types, and found in particular that stretches experienced by BAV leaflets during closure differ from those of TAV leaflets in terms of both heterogeneity as well as overall magnitude. Deformation is a key parameter in the clinical assessment of valvular function, and serves as a direct means to determine regional variations in structure and function. This study is an essential step toward patient-specific assessment of BAV based on correlating leaflet deformation and AS/AI progression, as it provides a means for assessing patient-specific stretch patterns.

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial.

Importance: Chronic pain is debilitating and profoundly affects health-related quality of life. Spinal cord stimulation (SCS) is a well-established therapy for chronic pain; however, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the evoked compound action potentials (ECAPs) to produce a real-time physiological closed-loop control system. Objective: To determine whether ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant. Design, Setting, and Participants: The Evoke study was a double-blind, randomized, controlled, parallel arm clinical trial with 36 months of follow-up. Participants were enrolled from February 2017 to 2018, and the study was conducted at 13 US investigation sites. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain visual analog scale score of 60 mm or more; Oswestry Disability Index score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021. Interventions: ECAP-controlled, closed-loop SCS was compared with fixed-output, open-loop SCS. Main Outcomes and Measures: Reported here are the 24-month outcomes of the trial, which include all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50% or more in overall back and leg pain assessed at 3 and 12 months (previously published). Results: Of 134 randomized patients, 65 (48.5%) were female and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (≥50% reduction) in overall pain (53 of 67 [79.1%] in the closed-loop group; 36 of 67 [53.7%] in the open-loop group; difference, 25.4% [95% CI, 10.0%-40.8%]; P = .001). There was no difference in safety profiles between groups (difference in rate of study-related adverse events: 6.0 [95% CI, -7.8 to 19.7]). Improvements were also observed in health-related quality of life, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms. Conclusions and Relevance: ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes.

Magnetic susceptibility and R2* of myocardial reperfusion injury at 3T and 7T.

PURPOSE: Magnetic susceptibility (Δχ) alterations have shown association with myocardial infarction (MI) iron deposition, yet there remains limited understanding of the relationship between relaxation rates and susceptibility or the effect of magnetic field strength. Hence, Δχ and R2∗ in MI were compared at 3T and 7T. METHODS: Subacute MI was induced by coronary artery ligation in male Yorkshire swine. 3D multiecho gradient echo imaging was performed at 1-week postinfarction at 3T and 7T. Quantitative susceptibility mapping images were reconstructed using a morphology-enabled dipole inversion. R2∗ maps and quantitative susceptibility mapping were generated to assess the relationship between R2∗ , Δχ, and field strength. Infarct histopathology was investigated. RESULTS: Magnetic susceptibility was not significantly different across field strengths (7T: 126.8 ± 41.7 ppb; 3T: 110.2 ± 21.0 ppb, P = NS), unlike R2∗ (7T: 247.0 ± 14.8 Hz; 3T: 106.1 ± 6.5 Hz, P < .001). Additionally, infarct Δχ and R2∗ were significantly higher than remote myocardium. Magnetic susceptibility at 7T versus 3T had a significant association (ß = 1.02, R2 = 0.82, P < .001), as did R2∗ (ß = 2.35, R2 = 0.98, P < .001). Infarct pathophysiology and iron deposition were detected through histology and compared with imaging findings. CONCLUSION: R2∗ showed dependence and Δχ showed independence of field strength. Histology validated the presence of iron and supported imaging findings.

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.

The impact of myocardial compressibility on organ-level simulations of the normal and infarcted heart.

Myocardial infarction (MI) rapidly impairs cardiac contractile function and instigates maladaptive remodeling leading to heart failure. Patient-specific models are a maturing technology for developing and determining therapeutic modalities for MI that require accurate descriptions of myocardial mechanics. While substantial tissue volume reductions of 15-20% during systole have been reported, myocardium is commonly modeled as incompressible. We developed a myocardial model to simulate experimentally-observed systolic volume reductions in an ovine model of MI. Sheep-specific simulations of the cardiac cycle were performed using both incompressible and compressible tissue material models, and with synchronous or measurement-guided contraction. The compressible tissue model with measurement-guided contraction gave best agreement with experimentally measured reductions in tissue volume at peak systole, ventricular kinematics, and wall thickness changes. The incompressible model predicted myofiber peak contractile stresses approximately double the compressible model (182.8 kPa, 107.4 kPa respectively). Compensatory changes in remaining normal myocardium with MI present required less increase of contractile stress in the compressible model than the incompressible model (32.1%, 53.5%, respectively). The compressible model therefore provided more accurate representation of ventricular kinematics and potentially more realistic computed active contraction levels in the simulated infarcted heart. Our findings suggest that myocardial compressibility should be incorporated into future cardiac models for improved accuracy.

Altered Responsiveness to TGFß and BMP and Increased CD45+ Cell Presence in Mitral Valves Are Unique Features of Ischemic Mitral Regurgitation.

[Figure: see text].

Pre-surgical Prediction of Ischemic Mitral Regurgitation Recurrence Using In Vivo Mitral Valve Leaflet Strains.

Ischemic mitral regurgitation (IMR) is a prevalent cardiac disease associated with substantial morbidity and mortality. Contemporary surgical treatments continue to have limited long-term success, in part due to the complex and multi-factorial nature of IMR. There is thus a need to better understand IMR etiology to guide optimal patient specific treatments. Herein, we applied our finite element-based shape-matching technique to non-invasively estimate peak systolic leaflet strains in human mitral valves (MVs) from in-vivo 3D echocardiographic images taken immediately prior to and post-annuloplasty repair. From a total of 21 MVs, we found statistically significant differences in pre-surgical MV size, shape, and deformation patterns between the with and without IMR recurrence patient groups at 6 months post-surgery. Recurrent MVs had significantly less compressive circumferential strains in the anterior commissure region compared to the recurrent MVs (p = 0.0223) and were significantly larger. A logistic regression analysis revealed that average pre-surgical circumferential leaflet strain in the Carpentier A1 region independently predicted 6-month recurrence of IMR (optimal cutoff value - 18%, p = 0.0362). Collectively, these results suggest greater disease progression in the recurrent group and underscore the highly patient-specific nature of IMR. Importantly, the ability to identify such factors pre-surgically could be used to guide optimal treatment methods to reduce post-surgical IMR recurrence.

Multimodal image analysis and subvalvular dynamics in ischemic mitral regurgitation.

Background: The exact geometric pathogenesis of leaflet tethering in ischemic mitral regurgitation (IMR) and the relative contribution of each component of the mitral valve complex (MVC) remain largely unknown. In this study, we sought to further elucidate mitral valve (MV) leaflet remodeling and papillary muscle dynamics in an ovine model of IMR with magnetic resonance imaging (MRI) and 3-dimensional echocardiography (3DE). Methods: Multimodal imaging combining 3DE and MRI was used to analyze the MVC at baseline, 30 minutes post-myocardial infarction (MI), and 12 weeks post-MI in ovine IMR models. Advanced 3D imaging software was used to trace the MVC from each modality, and the tracings were verified against resected specimens. Results: 3DE MV remodeling was regionally heterogenous and observed primarily in the anterior leaflet, with significant increases in surface area, especially in A2 and A3. The posterior leaflet was significantly shortened in P2 and P3. Mean posteromedial papillary muscle (PMPM) volume was decreased from 1.9 ± 0.2 cm3 at baseline to 0.9 ± 0.3 cm3 at 12 weeks post-MI (P < .05). At 12 weeks post-MI, the PMPM was predominately displaced horizontally and outward along the intercommissural axis with minor apical displacement. The subvalvular contribution to tethering is a combination of unilateral movement, outward displacement, and degeneration of the PMPM. These findings have led to a proposed new framework for characterizing PMPM dynamics in IMR. Conclusions: This study provides new insights into the complex interrelated and regionally heterogenous valvular and subvalvular mechanisms involved in the geometric pathogenesis of IMR tethering.