The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review.

Background and Objective: Ischemia reperfusion injury (IRI) is often the underlying cause of endothelium breakdown and damage in cardiac or transplantation operations, which can lead to disastrous post-operative consequences. Recent studies of cluster of differentiation 38 (CD38) have identified its critical role in IRI. Our objective is to provide a comprehensive overview of CD38-mediated axis, pathways, and potential CD38 translational therapies for reducing inflammation associated with cardiopulmonary bypass (CPB) or thoracic transplantation and IRI. Methods: We conducted a review of the literature by performing a search of the PubMed database on 2 April 2023. To find relevant publications on CD38, we utilized the MeSH terms: "CD38" AND "Ischemia" OR "CD38" AND "Transplant" OR "CD38" AND "Heart" from 1990-2023. Additional papers were included if they were felt to be relevant but were not captured in the MeSH terms. We found 160 papers that met this criterion, and following screening, exclusion and consensus a total of 36 papers were included. Key Content and Findings: CD38 is most notably a nicotine adenine dinucleotide (NAD)+ glycohydrolase (NADase), and a generator of Ca2+ signaling secondary messengers. Ultimately, the release of these secondary messengers leads to the activation of important mediators of cellular death. In the heart and during thoracic transplantation, this pathway is intimately involved in a wide variety of injuries; namely the endothelium. In the heart, activation generally results in vasoconstriction, poor myocardial perfusion, and ultimately poor cardiac function. CD38 activation also prevents the accumulation of atherosclerotic disease. During transplantation, intracellular activation leads to infiltration of recipient innate immune cells, tissue edema, and ultimately primary graft dysfunction (PGD). Specifically, in heart transplantation, extracellular activation could be protective and improve allograft survival. Conclusions: The knowledge gap in understanding the molecular basis of IRI has prevented further development of novel therapies and treatments. The possible interaction of CD38 with CD39 in the endothelium, and the modulation of the CD38 axis may be a pathway to improve cardiovascular outcomes, heart and lung donor organ quality, and overall longevity.

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.

Dynamic Annular Modeling of the Unrepaired Complete Atrioventricular Canal Annulus.

BACKGROUND: Repair of complete atrioventricular canal (CAVC) is often complicated by atrioventricular valve regurgitation, particularly of the left-sided valve. Understanding the 3-dimensional (3D) structure of the atrioventricular canal annulus before repair may help to inform optimized repair. However, the 3D shape and movement of the CAVC annulus has been neither quantified nor rigorously compared with a normal mitral valve annulus. METHODS: The complete annuli of 43 patients with CAVC were modeled in 4 cardiac phases using transthoracic 3D echocardiograms and custom code. The annular structure was compared with the annuli of 20 normal pediatric mitral valves using 3D metrics and statistical shape analysis (Procrustes analysis). RESULTS: The unrepaired CAVC annulus varied in shape significantly throughout the cardiac cycle. Procrustes analysis visually demonstrated that the average normalized CAVC annular shape is more planar than the normal mitral annulus. Quantitatively, the annular height-to-valve width ratio of the native left CAVC atrioventricular valve was significantly lower than that of a normal mitral valve in all systolic phases (P < .001). CONCLUSIONS: The left half of the CAVC annulus is more planar than that of a normal mitral valve with an annular height-to-valve width ratio similar to dysfunctional mitral valves. Given the known importance of annular shape to mitral valve function, further exploration of the association of 3D structure to valve function in CAVC is warranted.

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.

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.

Semi-automated Image Segmentation of the Midsystolic Left Ventricular Mitral Valve Complex in Ischemic Mitral Regurgitation.

Ischemic mitral regurgitation (IMR) is primarily a left ventricular disease in which the mitral valve is dysfunctional due to ventricular remodeling after myocardial infarction. Current automated methods have focused on analyzing the mitral valve and left ventricle independently. While these methods have allowed for valuable insights into mechanisms of IMR, they do not fully integrate pathological features of the left ventricle and mitral valve. Thus, there is an unmet need to develop an automated segmentation algorithm for the left ventricular mitral valve complex, in order to allow for a more comprehensive study of this disease. The objective of this study is to generate and evaluate segmentations of the left ventricular mitral valve complex in pre-operative 3D transesophageal echocardiography using multi-atlas label fusion. These patient-specific segmentations could enable future statistical shape analysis for clinical outcome prediction and surgical risk stratification. In this study, we demonstrate a preliminary segmentation pipeline that achieves an average Dice coefficient of 0.78 ± 0.06.

Dynamic Three-Dimensional Geometry of the Tricuspid Valve Annulus in Hypoplastic Left Heart Syndrome with a Fontan Circulation.

BACKGROUND: Tricuspid regurgitation (TR) is a significant contributor to morbidity and mortality in patients with hypoplastic left heart syndrome. The goal of this study was to characterize the dynamic annular motion of the tricuspid valve in patients with HLHS with a Fontan circulation and assess the relation to tricuspid valve function. METHODS: Tricuspid annuli of 48 patients with HLHS with a Fontan circulation were modeled at end-diastole, mid-systole, end-systole, and mid-diastole using transthoracic three-dimensional echocardiography and custom code in 3D Slicer. The angle of the anterior papillary muscle (APM) relative to the annular plane in each systolic phase was also measured. RESULTS: Imaging was performed 5.0 years (interquartile range, 2-11 years) after Fontan operation. The tricuspid annulus varies in shape significantly throughout the cardiac cycle, changing in sphericity (P < .001) but not in annular height or bending angle. In univariate modeling, patients with significant TR had larger changes in septolateral diameter, lateral quadrant area, and posterior quadrant area (P < .05 for all) as well as lower (more laterally directed) APM angles (P < .001) than patients with mild or less TR. In multivariate modeling, a 1 mm/(body surface area)0.5 increase in the maximum change in septolateral diameter was associated with a 1.7-fold increase in having moderate or greater TR, while a 10° decrease in APM angle at mid-systole was associated with an almost 2.5-fold increase in moderate or greater TR (P ≤ .01 for all). CONCLUSIONS: The tricuspid annulus in patients with HLHS with a Fontan circulation changes in shape significantly throughout the cardiac cycle but remains relatively planar. Increased change in septolateral diameter and decreased APM angle are strongly associated with the presence of TR. These findings may inform annuloplasty methods and subvalvular interventions in these complex patients.

Spatiotemporal Segmentation and Modeling of the Mitral Valve in Real-Time 3D Echocardiographic Images.

Transesophageal echocardiography is the primary imaging modality for preoperative assessment of mitral valves with ischemic mitral regurgitation (IMR). While there are well known echocardiographic insights into the 3D morphology of mitral valves with IMR, such as annular dilation and leaflet tethering, less is understood about how quantification of valve dynamics can inform surgical treatment of IMR or predict short-term recurrence of the disease. As a step towards filling this knowledge gap, we present a novel framework for 4D segmentation and geometric modeling of the mitral valve in real-time 3D echocardiography (rt-3DE). The framework integrates multi-atlas label fusion and template-based medial modeling to generate quantitatively descriptive models of valve dynamics. The novelty of this work is that temporal consistency in the rt-3DE segmentations is enforced during both the segmentation and modeling stages with the use of groupwise label fusion and Kalman filtering. The algorithm is evaluated on rt-3DE data series from 10 patients: five with normal mitral valve morphology and five with severe IMR. In these 10 data series that total 207 individual 3DE images, each 3DE segmentation is validated against manual tracing and temporal consistency between segmentations is demonstrated. The ultimate goal is to generate accurate and consistent representations of valve dynamics that can both visually and quantitatively provide insight into normal and pathological valve function.

Image Segmentation and Modeling of the Pediatric Tricuspid Valve in Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a single-ventricle congenital heart disease that is fatal if left unpalliated. In HLHS patients, the tricuspid valve is the only functioning atrioventricular valve, and its competence is therefore critical. This work demonstrates the first automated strategy for segmentation, modeling, and morphometry of the tricuspid valve in transthoracic 3D echocardiographic (3DE) images of pediatric patients with HLHS. After initial landmark placement, the automated segmentation step uses multi-atlas label fusion and the modeling approach uses deformable modeling with medial axis representation to produce patient-specific models of the tricuspid valve that can be comprehensively and quantitatively assessed. In a group of 16 pediatric patients, valve segmentation and modeling attains an accuracy (mean boundary displacement) of 0.8 ± 0.2 mm relative to manual tracing and shows consistency in annular and leaflet measurements. In the future, such image-based tools have the potential to improve understanding and evaluation of tricuspid valve morphology in HLHS and guide strategies for patient care.