A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration.

Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.

Dedifferentiation and Proliferation of Artery Endothelial Cells Drive Coronary Collateral Development in Mice.

BACKGROUND: Collateral arteries act as natural bypasses which reroute blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called artery reassembly, aids complete cardiac regeneration in neonatal hearts but is absent in adults. The reason for this age-dependent disparity in artery cell response is completely unknown. In this study, we investigated if regenerative potential of coronary arteries is dictated by their ability to dedifferentiate. METHODS: Single-cell RNA sequencing of coronary endothelial cells was performed to identify differences in molecular profiles of neonatal and adult endothelial cells in mice. Findings from this in silico analyses were confirmed with in vivo experiments using genetic lineage tracing, whole organ immunostaining, confocal imaging, and cardiac functional assays in mice. RESULTS: Upon coronary occlusion, neonates showed a significant increase in actively cycling artery cells and expressed prominent dedifferentiation markers. Data from in silico pathway analyses and in vivo experiments suggested that upon myocardial infarction, cell cycle reentry of preexisting neonatal artery cells, the subsequent collateral artery formation, and recovery of cardiac function are dependent on arterial VegfR2 (vascular endothelial growth factor receptor-2). This subpopulation of dedifferentiated and proliferating artery cells was absent in nonregenerative postnatal day 7 or adult hearts. CONCLUSIONS: These data indicate that adult artery endothelial cells fail to drive collateral artery development due to their limited ability to dedifferentiate and proliferate.

Integration of Reinforcement Learning in a Virtual Robotic Surgical Simulation.

Background. The revolutions in AI hold tremendous capacity to augment human achievements in surgery, but robust integration of deep learning algorithms with high-fidelity surgical simulation remains a challenge. We present a novel application of reinforcement learning (RL) for automating surgical maneuvers in a graphical simulation.Methods. In the Unity3D game engine, the Machine Learning-Agents package was integrated with the NVIDIA FleX particle simulator for developing autonomously behaving RL-trained scissors. Proximal Policy Optimization (PPO) was used to reward movements and desired behavior such as movement along desired trajectory and optimized cutting maneuvers along the deformable tissue-like object. Constant and proportional reward functions were tested, and TensorFlow analytics was used to informed hyperparameter tuning and evaluate performance.Results. RL-trained scissors reliably manipulated the rendered tissue that was simulated with soft-tissue properties. A desirable trajectory of the autonomously behaving scissors was achieved along 1 axis. Proportional rewards performed better compared to constant rewards. Cumulative reward and PPO metrics did not consistently improve across RL-trained scissors in the setting for movement across 2 axes (horizontal and depth).Conclusion. Game engines hold promising potential for the design and implementation of RL-based solutions to simulated surgical subtasks. Task completion was sufficiently achieved in one-dimensional movement in simulations with and without tissue-rendering. Further work is needed to optimize network architecture and parameter tuning for increasing complexity.

Diminishing Basic Science Research Experience Among United States Cardiothoracic Surgery Trainees.

INTRODUCTION: There is growing concern regarding the attrition of surgeon-scientists. To understand the decline of basic science research (BSR), it is essential to examine trends in research conducted by trainees. We hypothesized that, over recent decades, cardiothoracic (CT) surgery trainees have published fewer BSR articles. MATERIALS AND METHODS: CT surgeons at United States training institutions in 2020 who completed training in the past three decades, excluding international trainees, were analyzed (1991-2000: n = 148; 2001-2010: n = 228; 2011-2020: n = 247). Publication records were obtained from Scopus. Articles with medical subject heading terms involving molecular/cellular or animal research were classified as BSR using the National Institutes of Health iCite Translation module. Data were analyzed using Fisher's exact test or the Wilcoxon rank-sum test. RESULTS: While the proportion of surgeons who published a first-author paper during training remained stable over the past two decades (178/228 [78.1%] versus 189/247 [76.5%], P = 0.7427), the proportion who published a first-author BSR paper decreased significantly (135/228 [59.2%] versus 96/247 [38.9%], P < 0.0001). Among surgeons who published a first-author paper in training, the total papers published by each trainee did not change over the past two decades (3.5 versus 3.3 first-author papers per 10 y of training, P = 0.8819). However, the number of BSR papers published during training decreased significantly (1.7 versus 0.8 first-author papers per 10 y of training, P < 0.0001). CONCLUSIONS: CT surgery trainees are publishing fewer BSR papers. Additional efforts are needed to increase exposure of trainees to BSR and reaffirm that BSR is a valuable and worthwhile pursuit for academic surgeons.

Analyzing the Scholarly Impact of Cardiothoracic Surgery Research Using the Relative Citation Ratio.

INTRODUCTION: The National Institutes of Health (NIH) recently developed the relative citation ratio (RCR), calculated as article citations benchmarked to NIH-funded publications in the same field. Here, we characterized the scholarly impact of academic cardiothoracic (CT) surgeons and their research using the RCR. MATERIALS AND METHODS: Using a database of 992 CT surgeons, we calculated the RCR for all articles published by each surgeon since 1980 using the NIH iCite database. All data were collected from publicly available online sources. Data are presented as median (interquartile range) or as odds ratios (ORs) for multivariable logistic regression analysis. RESULTS: Where RCR 1.00 indicates equal impact as an NIH-funded publication, the RCR among all 37,402 CT surgery articles was 0.84 (0.33-1.83) and the RCR among NIH-funded CT surgery articles was 1.07 (0.53-2.17). CT surgeons exhibited a career median RCR of 0.82 (0.54-1.13) and maximum RCR of 6.20 (3.04-13.57). Predictors of career median RCR >1.00 included female gender (OR 2.23, P = 0.001), thoracic subspecialization (OR 2.50, P < 0.001), full professor rank (OR 1.89, P = 0.001), and NIH funding (OR 1.75, P = 0.001). Predictors of career maximum RCR >50th percentile among CT surgeons included male gender (OR 1.87, P = 0.030), thoracic subspecialization (OR 2.05, P < 0.001), full professor rank (OR 4.89, P < 0.001), NIH funding (OR 3.17, P < 0.001), and career duration (OR 1.03, P = 0.002). CONCLUSIONS: We present the first assessment of the NIH-validated RCR for academic CT surgery. CT surgery research is highly impactful, although gender disparities persist with respect to the highest-impact research of our specialty.

Post-Transplant Extracorporeal Membrane Oxygenation for Severe Primary Graft Dysfunction to Support the Use of Marginal Donor Hearts.

Severe primary graft dysfunction (PGD) is the leading cause of early postoperative mortality following orthotopic heart transplantation (OHT). Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used as salvage therapy. This study aimed to evaluate the outcomes in adult OHT recipients who underwent VA-ECMO for severe PGD. We retrospectively reviewed 899 adult (≥18 years) patients who underwent primary OHT at our institution between 1997 and 2017. Recipients treated with VA-ECMO (19, 2.1%) exhibited a higher incidence of previous cardiac surgery (p = .0220), chronic obstructive pulmonary disease (p = .0352), and treatment with a calcium channel blocker (p = .0018) and amiodarone (p = .0148). Cardiopulmonary bypass (p = .0410) and aortic cross-clamp times (p = .0477) were longer in the VA-ECMO cohort and they were more likely to have received postoperative transfusion (p = .0013); intra-aortic balloon pump (IABP, p < .0001), and reoperation for bleeding or tamponade (p < .0001). The 30-day, 1-year, and overall survival after transplantation of non-ECMO patients were 95.9, 88.8, and 67.4%, respectively, compared to 73.7, 57.9, and 47.4%, respectively in the ECMO cohort. Fourteen (73.7%) of the ECMO patients were weaned after a median of 7 days following OHT (range: 1-12 days). Following OHT, VA-ECMO may be a useful salvage therapy for severe PGD and can potentially support the usage of marginal donor hearts.

Impact of PhD Degree Versus Non-PhD Research Fellowship on Future Research Productivity Among Academic Cardiothoracic Surgeons.

BACKGROUND: A PhD degree can offer significant research experience, but previous studies yielded conflicting conclusions on the relationship between a PhD degree and future research output. We compared the impact of a PhD degree versus research fellowship (RF) training on research productivity in cardiothoracic surgeons, hypothesizing that training pathways may influence potential associations. METHODS: CT surgeons practicing at all accredited United States CT surgery training programs in 2018 who pursued dedicated time for research (n = 597), including earning a PhD degree (n = 92) or completing a non-PhD RF (n = 505), were included. To control for training pathways, we performed subanalyses of U.S. medical school graduates (n = 466) and international medical school graduates (IMGs) (n = 131). Surgeon-specific data were obtained from publicly available sources (e.g., institutional webpages, Scopus). RESULTS: PhD surgeons published greater total papers (68.5 vs. 52.0, p = 0.0179) and total papers per year as an attending (4.6 vs. 3.0, p = 0.0150). For U.S. medical school graduates, there were 40 PhD surgeons and 426 non-PhD RF surgeons; both groups published a similar number of total papers (64.5 vs. 54.0, p = 0.3738) and total papers per year (3.2 vs. 3.0, p = 0.7909). For IMGs, there were 52 PhD surgeons and 79 non-PhD RF surgeons; the PhD surgeons published greater total papers (80.5 vs. 45.0, p = 0.0101) and total papers per year (5.7 vs. 2.7, p = 0.0037). CONCLUSION: CT surgeons with dedicated research training are highly academically productive. Although a PhD degree may be associated with enhanced career-long research productivity for IMGs, this association was not observed for U.S. medical school graduates.

Comprehensive Ex Vivo Comparison of 5 Clinically Used Conduit Configurations for Valve-Sparing Aortic Root Replacement Using a 3-Dimensional-Printed Heart Simulator.

BACKGROUND: Many graft configurations are clinically used for valve-sparing aortic root replacement, some specifically focused on recapitulating neosinus geometry. However, the specific impact of such neosinuses on valvular and root biomechanics and the potential influence on long-term durability are unknown. METHODS: Using a custom 3-dimenstional-printed heart simulator with porcine aortic roots (n=5), the anticommissural plication, Stanford modification, straight graft (SG), Uni-Graft, and Valsalva graft configurations were tested in series using an incomplete counterbalanced measures design, with the native root as a control, to mitigate ordering effects. Hemodynamic and videometric data were analyzed using linear models with conduit as the fixed effect of interest and valve as a fixed nuisance effect with post hoc pairwise testing using Tukey's correction. RESULTS: Hemodynamics were clinically similar between grafts and control aortic roots. Regurgitant fraction varied between grafts, with SG and Uni-Graft groups having the lowest regurgitant fractions and anticommissural plication having the highest. Root distensibility was significantly lower in SG versus both control roots and all other grafts aside from the Stanford modification (P≤0.01 for each). All grafts except SG had significantly higher cusp opening velocities versus native roots (P<0.01 for each). Relative cusp opening forces were similar between SG, Uni-Graft, and control groups, whereas anticommissural plication, Stanford modification, and Valsalva grafts had significantly higher opening forces versus controls (P<0.01). Cusp closing velocities were similar between native roots and the SG group, and were significantly lower than observed in the other conduits (P≤0.01 for each). Only SG and Uni-Graft groups experienced relative cusp closing forces approaching that of the native root, whereas relative forces were >5-fold higher in the anticommissural plication, Stanford modification, and Valsalva graft groups. CONCLUSIONS: In this ex vivo modeling system, clinically used valve-sparing aortic root replacement conduit configurations have comparable hemodynamics but differ in biomechanical performance, with the straight graft most closely recapitulating native aortic root biomechanics.

Characterization of Cardiothoracic Surgeons Actively Leading Basic Science Research.

BACKGROUND: There is increasing concern regarding the attrition of surgeon-scientists in cardiothoracic (CT) surgery. However, the characteristics of CT surgeons who are actively leading basic science research (BSR) have not been examined. We hypothesized that early exposure to BSR during training and active grant funding are important factors that facilitate the pursuit of BSR among practicing CT surgeons. MATERIALS AND METHODS: We created a database of 992 CT surgeons listed as faculty at accredited United States CT surgery teaching hospitals in 2018. Data regarding each surgeon's training/professional history, publication record, and National Institutes of Health funding were acquired from publicly available online sources. Surgeons who published at least one first- or last-author paper in 2017-2018 were considered to be active, lead researchers. RESULTS: Of the 992 CT surgeons, 73 (7.4%) were actively leading BSR, and 599 (60.4%) were actively leading only non-BSR. Only 2 women were actively leading BSR. Surgeons actively leading BSR were more likely to have earned a PhD degree (20.5% versus 9.7%, P = 0.0049), and more likely to have published a first-author BSR paper during training (76.7% versus 40.9%, P< 0.0001). Surgeons actively leading BSR were also more likely to have an active National Institutes of Health grant (34.2% versus 5.8%, P< 0.0001), especially an R01 grant (21.9% versus 2.5%, P< 0.0001). CONCLUSIONS: A small minority of CT surgeons at academic training hospitals are actively leading BSR. In order to facilitate the development of surgeon-scientists, additional support must be given to trainees and junior faculty, especially women, to enable early engagement in BSR.

Career Research Productivity Correlates With Medical School Ranking Among Cardiothoracic Surgeons.

BACKGROUND: The foundation for a successful academic surgical career begins in medical school. We examined whether attending a top-ranked medical school is correlated with enhanced research productivity and faster career advancement among academic cardiothoracic (CT) surgeons. MATERIALS AND METHODS: Research profiles and professional histories were obtained from publicly available sources for all CT surgery faculty at accredited US CT surgery teaching hospitals in 2018 (n = 992). We focused on surgeons who completed medical school in the United States during or after 1990, the first-year US News & World Report released its annual medical school research rankings (n = 451). Subanalyses focused on surgeons who completed a research fellowship (n = 299) and those who did not (n = 152). RESULTS: A total of 124 surgeons (27.5%) attended a US News & World Report top 10 medical school, whereas 327 (72.5%) did not. Surgeons who studied at a top 10 medical school published more articles per year as an attending surgeon (3.2 versus 1.9; P < 0.0001), leading to more total publications (51.5 versus 27.0; P < 0.0001) and a higher H-index (16.0 versus 11.0; P < 0.0001) over a similar career duration (11.0 versus 10.0 y; P = 0.1294). These differences in career-long research productivity were statistically significant regardless of whether the surgeons completed a research fellowship or not. The surgeons in both groups, however, required a similar number of years to reach associate professor rank (P = 0.6993) and full professor rank (P = 0.7811) after starting their first attending job. CONCLUSIONS: Attending a top-ranked medical school is associated with enhanced future research productivity but not with faster career advancement in academic CT surgery.

The Use of Factor Eight Inhibitor Bypass Activity (FEIBA) for the Treatment of Perioperative Hemorrhage in Left Ventricular Assist Device Implantation.

OBJECTIVE: To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis. DESIGN: Retrospective cohort study. SETTING: Academic hospital. PARTICIPANTS: Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018). INTERVENTION: FEIBA administered to control perioperative hemorrhage. MEASUREMENTS AND MAIN RESULTS: The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 × 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk. CONCLUSIONS: In this retrospective cohort study, the use of FEIBA (∼1,000 units, ∼13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.

Successful beating-heart repair of pulmonary artery dissection using a composite valve-tube graft.

Pulmonary artery dissection is rare but highly lethal. Recent reports suggest that surgical repair of pulmonary artery dissection may yield good outcomes in selected patients, although postoperative right ventricular failure and death have been described. Currently, only one patient over age 60 years old has been reported to survive open surgical repair of pulmonary artery dissection. Here, we present the case of a sexagenarian with pulmonary artery hypertension complicated by a dissected pulmonary artery aneurysm which was successfully repaired using a composite valve-tube graft under a beating-heart strategy.

Evaluation of Risk Factors for Heart-Lung Transplant Recipient Outcome: An Analysis of the United Network for Organ Sharing Database.

BACKGROUND: Heart-lung transplantation (HLTx) is an effective treatment for patients with advanced cardiopulmonary failure. However, no large multicenter study has focused on the relationship between donor and recipient risk factors and post-HLTx outcomes. Thus, we investigated this issue using data from the United Network for Organ Sharing database. METHODS: All adult patients (age ≥18 years) registered in the United Network for Organ Sharing database who underwent HLTx between 1987 and 2017 were included (n=997). We stratified the cohort by patients who were alive without retransplant at 1 year (n=664) and patients who died or underwent retransplant within 1 year of HLTx (n=333). The primary outcome was the influence of donor and recipient characteristics on 1-year post-HLTx recipient death or retransplant. Kaplan-Meier curves were created to assess overall freedom from death or retransplant. To obtain a better effect estimation on hazard and survival time, the parametric Accelerated Failure Time model was chosen to perform time-to-event modeling analyses. RESULTS: Overall graft survival at 1-year post-HLTx was 66.6%. Of donors, 53% were male, and the mean age was 28.2 years. Univariable analysis showed advanced donor age, recipient male sex, recipient creatinine, recipient history of prior cardiac or lung surgery, recipient extracorporeal membrane oxygenation support, transplant year, and transplant center volume were associated with 1-year post-HLTx death or retransplant. On multivariable analysis, advanced donor age (hazard ratio [HR], 1.017; P=0.0007), recipient male sex (HR, 1.701; P=0.0002), recipient extracorporeal membrane oxygenation support (HR, 4.854; P<0.0001), transplant year (HR, 0.962; P<0.0001), and transplantation at low-volume (HR, 1.694) and medium-volume centers (HR, 1.455) in comparison with high-volume centers (P=0.0007) remained as significant predictors of death or retransplant. These predictors were incorporated into an equation capable of estimating the preliminary probability of graft survival at 1-year post-HLTx on the basis of preoperative factors alone. CONCLUSIONS: HLTx outcomes may be improved by considering the strong influence of donor age, recipient sex, recipient hemodynamic status, and transplant center volume. Marginal donors and recipients without significant factors contributing to poor post-HLTx outcomes may still be considered for transplantation, potentially with less impact on the risk of early postoperative death or retransplant.

Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model.

Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.

Development and Ex Vivo Validation of Novel Force-Sensing Neochordae for Measuring Chordae Tendineae Tension in the Mitral Valve Apparatus Using Optical Fibers With Embedded Bragg Gratings.

Few technologies exist that can provide quantitative data on forces within the mitral valve apparatus. Marker-based strain measurements can be performed, but chordal geometry and restricted optical access are limitations. Foil-based strain sensors have been described and work well, but the sensor footprint limits the number of chordae that can be measured. We instead utilized fiber Bragg grating (FBG) sensors-optical strain gauges made of 125 µm diameter silica fibers-to overcome some limitations of previous methods of measuring chordae tendineae forces. Using FBG sensors, we created a force-sensing neochord (FSN) that mimics the natural shape and movement of native chordae. FBG sensors reflect a specific wavelength of light depending on the spatial period of gratings. When force is applied, the gratings move relative to one another, shifting the wavelength of reflected light. This shift is directly proportional to force applied. The FBG sensors were housed in a protective sheath fashioned from a 0.025 in. flat coil, and attached to the chordae using polytetrafluoroethylene suture. The function of the force-sensing neochordae was validated in a three-dimensional (3D)-printed left heart simulator, which demonstrated that FBG sensors provide highly sensitive force measurements of mitral valve chordae at a temporal resolution of 1000 Hz. As ventricular pressures increased, such as in hypertension, chordae forces also increased. Overall, FBG sensors are a viable, durable, and high-fidelity sensing technology that can be effectively used to measure mitral valve chordae forces and overcome some limitations of other such technologies.

Second Arterial Versus Venous Conduits for Multivessel Coronary Artery Bypass Surgery in California.

BACKGROUND: Whether a second arterial conduit improves outcomes after multivessel coronary artery bypass grafting remains unclear. Consequently, arterial conduits other than the left internal thoracic artery are seldom used in the United States. METHODS: Using a state-maintained clinical registry including all 126 nonfederal hospitals in California, we compared all-cause mortality and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score-matched cohorts who underwent primary, isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit (right internal thoracic artery or radial artery, n=5866) or a venous conduit (n=53 566) between 2006 and 2011. Propensity score matching using 34 preoperative characteristics yielded 5813 matched sets. A subgroup analysis compared outcomes between propensity score-matched recipients of a right internal thoracic artery (n=1576) or a radial artery (n=4290). RESULTS: Second arterial conduit use decreased from 10.7% in 2006 to 9.1% in 2011 (P<0.0001). However, receipt of a second arterial conduit was associated with significantly lower mortality (13.1% versus 10.6% at 7 years; hazard ratio, 0.79; 95% confidence interval [CI], 0.72-0.87), and lower risks of myocardial infarction (hazard ratio, 0.78; 95% CI, 0.70-0.87) and repeat revascularization (hazard ratio, 0.82; 95% CI, 0.76-0.88). In comparison with radial artery grafts, right internal thoracic artery grafts were associated with similar mortality rates (right internal thoracic artery 10.3% versus radial artery 10.7% at 7 years; hazard ratio, 1.10; 95% CI, 0.89-1.37) and individual risks of cardiovascular events, but the risk of sternal wound infection was increased (risk difference, 1.07%; 95% CI, 0.15-2.07). CONCLUSIONS: Second arterial conduit use in California is low and declining, but arterial grafts were associated with significantly lower mortality and fewer cardiovascular events. A right internal thoracic artery graft offered no benefit over that of a radial artery, but did increase risk of sternal wound infection. These findings suggest surgeons should consider lowering their threshold for using arterial grafts, and the radial artery may be the preferred second conduit.

Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets.

BACKGROUND: Cardiovascular bypass grafting is an essential treatment for complex cases of atherosclerotic disease. Because the availability of autologous arterial and venous conduits is patient-limited, self-assembled cell-only grafts have been developed to serve as functional conduits with off-the-shelf availability. The unacceptably long production time required to generate these conduits, however, currently limits their clinical utility. Here, we introduce a novel technique to significantly accelerate the production process of self-assembled engineered vascular conduits. METHODS: Human aortic smooth muscle cells and skin fibroblasts were used to construct bilevel cell sheets. Cell sheets were wrapped around a 22.5-gauge Angiocath needle to form tubular vessel constructs. A thin, flexible membrane of clinically approved biodegradable tissue glue (Dermabond Advanced) served as a temporary, external scaffold, allowing immediate perfusion and endothelialization of the vessel construct in a bioreactor. Subsequently, the matured vascular conduits were used as femoral artery interposition grafts in rats (n=20). Burst pressure, vasoreactivity, flow dynamics, perfusion, graft patency, and histological structure were assessed. RESULTS: Compared with engineered vascular conduits formed without external stabilization, glue membrane-stabilized conduits reached maturity in the bioreactor in one-fifth the time. After only 2 weeks of perfusion, the matured conduits exhibited flow dynamics similar to that of control arteries, as well as physiological responses to vasoconstricting and vasodilating drugs. The matured conduits had burst pressures exceeding 500 mm Hg and had sufficient mechanical stability for surgical anastomoses. The patency rate of implanted conduits at 8 weeks was 100%, with flow rate and hind-limb perfusion similar to those of sham controls. Grafts explanted after 8 weeks showed a histological structure resembling that of typical arteries, including intima, media, adventitia, and internal and external elastic membrane layers. CONCLUSIONS: Our technique reduces the production time of self-assembled, cell sheet-derived engineered vascular conduits to 2 weeks, thereby permitting their use as bypass grafts within the clinical time window for elective cardiovascular surgery. Furthermore, our method uses only clinically approved materials and can be adapted to various cell sources, simplifying the path toward future clinical translation.

Utilization of Del Nido Cardioplegia in Adult Coronary Artery Bypass Grafting　- A Retrospective Analysis.

BACKGROUND: Studies assessing the safety and effectiveness of Del Nido cardioplegia for adult cardiac surgery remain limited. We investigated early outcomes after coronary artery bypass grafting (CABG) using single-dose Del Nido cardioplegia vs. conventional multi-dose blood cardioplegia. Methods and Results: The 81 consecutive patients underwent isolated CABG performed by a single surgeon. The initial 27 patients received anterograde blood cardioplegia, while the subsequent 54 patients received anterograde Del Nido cardioplegia. There were no differences in the baseline characteristics of each group nor any differences in the 30-day incidences of myocardial infarction, all-cause death, and readmission following surgery. The use of Del Nido cardioplegia was associated with shorter cardiopulmonary bypass time (98 vs. 115 min, P=0.011), shorter cross-clamp time (74 vs. 87 min, P=0.006), and decreased need for intraoperative defibrillation (13.0% vs. 33.3%, P=0.030) compared with blood cardioplegia. To control for the difference in cross-clamp time, we performed propensity score matching with a logistical treatment model and confirmed that Del Nido cardioplegia provided similar outcomes as blood cardioplegia and also reduced the need for defibrillation independent of cross-clamp time. CONCLUSIONS: Compared with conventional blood cardioplegia, Del Nido cardioplegia provided excellent myocardial protection with reduced need for intraoperative defibrillation, shorter bypass and cross-clamp times, and comparable early clinical outcomes for adult patients undergoing CABG.

Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy.

BACKGROUND: Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM. METHODS: Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle). RESULTS: SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group. CONCLUSIONS: Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.

Structural, angiogenic, and immune responses influencing myocardial regeneration: a glimpse into the crucible.

Complete cardiac regeneration remains an elusive therapeutic goal. Although much attention has been focused on cardiomyocyte proliferation, especially in neonatal mammals, recent investigations have unearthed mechanisms by which non-cardiomyocytes, such as endothelial cells, fibroblasts, macrophages, and other immune cells, play critical roles in modulating the regenerative capacity of the injured heart. The degree to which each of these cell types influence cardiac regeneration, however, remains incompletely understood. This review highlights the roles of these non-cardiomyocytes and their respective contributions to cardiac regeneration, with emphasis on natural heart regeneration after cardiac injury during the neonatal period.