Development of a Novel Hierarchically Biofabricated Blood Vessel Mimic Decorated with Three Vascular Cell Populations for the Reconstruction of Small-Diameter Arteries.

The availability of grafts to replace small-diameter arteries remains an unmet clinical need. Here, the validated methodology is reported for a novel hybrid tissue-engineered vascular graft that aims to match the natural structure of small-size arteries. The blood vessel mimic (BVM) comprises an internal conduit of co-electrospun gelatin and polycaprolactone (PCL) nanofibers (corresponding to the tunica intima of an artery), reinforced by an additional layer of PCL aligned fibers (the internal elastic membrane). Endothelial cells are deposited onto the luminal surface using a rotative bioreactor. A bioprinting system extrudes two concentric cell-laden hydrogel layers containing respectively vascular smooth muscle cells and pericytes to create the tunica media and adventitia. The semi-automated cellularization process reduces the production and maturation time to 6 days. After the evaluation of mechanical properties, cellular viability, hemocompatibility, and suturability, the BVM is successfully implanted in the left pulmonary artery of swine. Here, the BVM showed good hemostatic properties, capability to withstand blood pressure, and patency at 5 weeks post-implantation. These promising data open a new avenue to developing an artery-like product for reconstructing small-diameter blood vessels.

Growth capacity of a Wharton's Jelly derived mesenchymal stromal cells tissue engineered vascular graft used for main pulmonary artery reconstruction in piglets.

Background: Surgical treatment of congenital heart defects affecting the right ventricular outflow tract (RVOT) often requires complex reconstruction and multiple reoperations due to structural degeneration and lack of growth of currently available materials. Hence, alternative approaches for RVOT reconstruction, which meet the requirements of biocompatibility and long-term durability of an ideal scaffold, are needed. Through this full scale pre-clinical study, we demonstrated the growth capacity of a Wharton's Jelly derived mesenchymal stromal cells (WJ-MSC) tissue engineered vascular graft used in reconstructing the main pulmonary artery in piglets, providing proof of biocompatibility and efficacy. Methods: Sixteen four-week-old Landrace pigs were randomized to undergo supravalvar Main Pulmonary Artery (MPA) replacement with either unseeded or WJ-MSCs-seeded Small Intestinal Submucosa-derived grafts. Animals were followed up for 6 months by clinical examinations and cardiac imaging. At termination, sections of MPAs were assessed by macroscopic inspection, histology and fluorescent immunohistochemistry. Results: Data collected at 6 months follow up showed no sign of graft thrombosis or calcification. The explanted main pulmonary arteries demonstrated a significantly higher degree of cellular organization and elastin content in the WJ-MSCs seeded grafts compared to the acellular counterparts. Transthoracic echocardiography and cardiovascular magnetic resonance confirmed the superior growth and remodelling of the WJ-MSCs seeded conduit compared to the unseeded. Conclusion: Our findings indicate that the addition of WJ-MSCs to the acellular scaffold can upgrade the material, converting it into a biologically active tissue, with the potential to grow, repair and remodel the RVOT.

Outcome monitoring and risk stratification after cardiac procedure in neonates, infants, children and young adults born with congenital heart disease: protocol for a multicentre prospective cohort study (Children OMACp).

INTRODUCTION: Congenital heart disease (CHD) represents the most common birth defect, affecting from 0.4% to 1.2% of children born in developed countries. The survival of these patients has increased significantly, but CHD remains one of the major causes of neonatal and childhood death. The aetiology of CHD is complex, with some evidence of both genetic and environmental causes. However, there is still lack of knowledge regarding modifiable risk factors and molecular and genetic mechanisms underlying the development of CHD. This study aims to develop a prospective cohort of patients undergoing cardiac procedures that will bring together routinely collected clinical data and biological samples from patients and their biological mothers, in order to investigate risk factors and predictors of postoperative-outcomes, as well as better understanding the effect of the surgical intervention on the early and long-term outcomes. METHODS AND ANALYSIS: Children OMACp (OMACp, outcome monitoring after cardiac procedure in congenital heart disease) is a multicentre, prospective cohort study recruiting children with CHD undergoing a cardiac procedure. The study aims to recruit 3000 participants over 5 years (2019-2024) across multiple UK sites. Routine clinical data will be collected, as well as participant questionnaires collecting sociodemographic, NHS resource use and quality of life data. Biological samples (blood, urine and surgical waste tissue from patients, and blood and urine samples from biological mothers) will be collected where consent has been obtained. Follow-up outcome and questionnaire data will be collected for 5 years. ETHICS AND DISSEMINATION: The study was approved by the London-Brent Research Ethics Committee on 30 July 2019 (19/SW/0113). Participants (or their parent/guardian if under 16 years of age) must provide informed consent prior to being recruited into the study. Mothers who wish to take part must also provide informed consent prior to being recruited. The study is sponsored by University Hospitals Bristol and Weston Foundation Trust and is managed by the University of Bristol. Children OMACp is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated through peer-reviewed publications, presentation at conference, meetings and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN17650644.

The effect of cardioplegic supplementation with sildenafil on cardiac energetics in a piglet model of cardiopulmonary bypass and cardioplegic arrest with warm or cold cardioplegia.

Cardioplegic cardioprotection strategies used during paediatric open-heart surgery remain suboptimal. Sildenafil, a phosphodiesterase 5 (PDE-5) inhibitor, has been shown to be cardioprotective against ischemia/reperfusion injury in a variety of experimental models and this study therefore tested the efficacy of supplementation of cardioplegia with sildenafil in a piglet model of cardiopulmonary bypass and arrest, using both cold and warm cardioplegia protocols. Piglets were anaesthetized and placed on coronary pulmonary bypass (CPB), the aorta cross-clamped and the hearts arrested for 60 min with cardioplegia with or without sildenafil (10 nM). Twenty minutes after removal of cross clamp (reperfusion), attempts were made to wean the pigs from CPB. Termination was carried out after 60 min reperfusion. Throughout the protocol blood and left ventricular tissue samples were taken for analysis of selected metabolites (using HPLC) and troponin I. In both the cold and warm cardioplegia protocols there was evidence that sildenafil supplementation resulted in faster recovery of ATP levels, improved energy charge (a measure of metabolic flux) and altered release of hypoxanthine and inosine, two purine catabolites. There was no effect on troponin release within the studied short timeframe. In conclusion, sildenafil supplementation of cardioplegia resulted in improved cardiac energetics in a translational animal model of paediatric CPB surgery.

Wharton's Jelly-Mesenchymal Stem Cell-Engineered Conduit for Pulmonary Artery Reconstruction in Growing Piglets.

Surgical treatment of congenital heart defects affecting the right ventricular outflow tract often requires complex reconstruction and multiple reoperations. With a randomized controlled trial, we compared a novel tissue-engineered small intestine submucosa-based graft for pulmonary artery reconstruction (seeded with mesenchymal stem cells derived from Wharton's Jelly) with conventional small intestine submucosa in growing piglets. Six months after implantation, seeded grafts showed integration with host tissues at cellular level and exhibited growth potential on transthoracic echocardiography and cardiovascular magnetic resonance. Our seeded graft is a promising biomaterial for pulmonary artery reconstruction in pediatric patients with right ventricular outflow tract abnormalities.

Reconstruction of the Swine Pulmonary Artery Using a Graft Engineered With Syngeneic Cardiac Pericytes.

The neonatal heart represents an attractive source of regenerative cells. Here, we report the results of a randomized, controlled, investigator-blinded preclinical study, which assessed the safety and effectiveness of a matrix graft cellularized with cardiac pericytes (CPs) in a piglet model of pulmonary artery (PA) reconstruction. Within each of five trios formed by 4-week-old female littermate piglets, one element (the donor) was sacrificed to provide a source of CPs, while the other two elements (the graft recipients) were allowed to reach the age of 10 weeks. During this time interval, culture-expanded donor CPs were seeded onto swine small intestinal submucosa (SIS) grafts, which were then shaped into conduits and conditioned in a flow bioreactor. Control unseeded SIS conduits were subjected to the same procedure. Then, recipient piglets were randomized to surgical reconstruction of the left PA (LPA) with unseeded or CP-seeded SIS conduits. Doppler echocardiography and cardiac magnetic resonance imaging (CMRI) were performed at baseline and 4-months post-implantation. Vascular explants were examined using histology and immunohistochemistry. All animals completed the scheduled follow-up. No group difference was observed in baseline imaging data. The final Doppler assessment showed that the LPA's blood flow velocity was similar in the treatment groups. CMRI revealed a mismatch in the average growth of the grafted LPA and contralateral branch in both treatment groups. Histology of explanted arteries demonstrated that the CP-seeded grafts had a thicker luminal cell layer, more intraparietal arterioles, and a higher expression of endothelial nitric oxide synthase (eNOS) compared with unseeded grafts. Moreover, the LPA stump adjacent to the seeded graft contained more elastin and less collagen than the unseeded control. Syngeneic CP engineering did not accomplish the primary goal of supporting the graft's growth but was able to improve secondary outcomes, such as the luminal cellularization and intraparietal vascularization of the graft, and elastic remodeling of the recipient artery. The beneficial properties of neonatal CPs may be considered in future bioengineering applications aiming to reproduce the cellular composition of native arteries.

Allogeneic Mesenchymal Stromal Cell Injection to Alleviate Ischemic Heart Failure Following Arterial Switch Operation.

Cell therapy is a promising tool to prevent and treat heart failure in congenital heart disease. We report the first case of intramyocardial injection of allogeneic mesenchymal stromal cells as rescue therapy in a neonate with ischemic heart failure following arterial switch procedure for isolated transposition of the great arteries. (Level of Difficulty: Advanced.).

Benefits of mitral valve repair over replacement in the elderly: a systematic review and meta-analysis.

OBJECTIVES: Mitral valve (MV) repair has demonstrated excellent short- and long-term outcomes, however, its merit in the elderly population is still debated. We conducted a meta-analysis of studies that have compared the MV repair to replacement in the elderly population. METHODS: A systematic literature search was conducted for any study published on MV surgery on elderly patients (≥75 years old). A pooled risk-ratio meta-analysis was done to evaluate short-term mortality, postoperative complications, surgical timings, and long-term survival rates. RESULTS: A total of nine retrospective observational studies were included in the quantitative meta-analysis. Pooled meta-analysis showed a reduced risk of short-term mortality for the MV repair group (risk ratio [RR] = 0.41 [0.24-0.71], p-value = .005). Postoperative neurological complications were in favor of repair, although not significantly (RR = 0.49 [0.21-1.11], p-value = .07). Operative timings (cardiopulmonary bypass and crossclamp time) were not different between the groups although no data were available on the complexity of the repairs. Long-term survival rates were in favor of the repairs (pooled treatment effect of -0.47 [-0.64; -0.29], p = .005). CONCLUSIONS: MV surgery is a safe and effective procedure for the elderly. MV repair demonstrated better short-term outcomes compared to replacement. Long-term survival rates are significantly better after repair.

Adult coronary artery bypass grafting by congenital surgeons-a propensity matched analysis.

OBJECTIVES: Surgical myocardial revascularization will be increasingly needed in adult patients with congenital heart disease. We investigated the results of coronary artery bypass grafting (CABG) performed on adults by congenital cardiac surgeons at our institution. METHODS: We conducted a retrospective, single-centre study. Adults undergoing isolated or combined CABG from 2004 to 2017 were included. Early and late outcomes were analyzed for the whole cohort. Furthermore, a propensity matched analysis was conducted comparing the results of isolated CABG between congenital and adult surgeons. RESULTS: A total of 514 and 113 patients had isolated and combined CABG for acquired heart disease, respectively. A total of 33 patients had myocardial revascularization at the time of surgery for congenital heart disease. Overall early mortality was 1.2%, the rate of re-exploration for bleeding was 4.5%, and an internal mammary artery to left anterior descending artery graft was used in 85.6% patients. One-year survival was 97.5% (96.2-98.8%), and 5-year survival was 88.0% (84.8-91.3%). After propensity matching (468 pairs), early mortality (0.6% vs 1.2%, P = 0.51), re-exploration for bleeding (3.6% vs 3.0%, P = 0.72), use of internal mammary artery to left anterior descending artery graft (92.7% vs 91.9%, P = 0.70) and late survival did not differ between congenital surgeons and adult surgeons, respectively. CONCLUSIONS: Surgical myocardial revascularization can be required for adult congenital patients in a broad spectrum of clinical situations. Despite lower volumes, congenital cardiac surgeons perform CABG safely and with results that are comparable to those of the adult surgeons at our centre.

Body mass index and early outcomes following mitral valve surgery for degenerative disease.

OBJECTIVE: Using a large national database, we sought to better define the relationship between obesity measures and early clinical outcomes following mitral valve surgery for degenerative disease. METHODS: For the outcomes of in-hospital mortality, postoperative cerebrovascular event (CVA), and deep sternal wound infection (DSWI), a retrospective cohort study was performed using data acquired from the United Kingdom National Adult Cardiac Surgery Audit. Multivariable Cox proportional hazard regression modeling was used to investigate associations with individual measures of obesity. Progressively adjusted body mass index (BMI)-specific hazard ratios (HRs) were plotted against mean BMI values in each World Health Organization category using floated variances to investigate specific shapes of association. RESULTS: Multivariable Cox proportional hazard modeling failed to demonstrate an association between mortality and an increase in BMI of 5 points (HR, 0.93, 95% confidence interval [CI], 0.81-1.07), a BMI quintile increase (HR, 0.98; 95% CI, 0.90-1.07), or being classed "obese" by World Health Organization standards (HR, 1.03; 95% CI, 0.74-1.42). A 5-point BMI increase was associated with an increased hazard of DSWI (HR, 1.38; 95% CI, 1.08-1.77) but was not associated with perioperative CVA (HR, 1.05; 95% CI, 0.91-1.21). The shape of association between BMI and mortality appeared approximately U-shaped. DSWI appeared linear, whereas CVA demonstrated an inverted U, or a possible hourglass. CONCLUSIONS: Although individual measures of obesity were not associated with an increased mortality risk on regression modeling, the U-shaped relationship between mortality and increasing BMI demonstrates lower mortality risks in lower obesity classes. Increasing BMI was associated with an increased hazard for DSWI.

Wharton's Jelly-Mesenchymal Stem Cell-Engineered Conduit for Pediatric Translation in Heart Defect.

The materials available for the right ventricular outflow tract (RVOT) reconstruction in patients with tetralogy of fallot (TOF)/pulmonary atresia come with the severe limitation of long-term degeneration and lack of growth potential, causing right ventricular dysfunction, aneurysm formation, and arrhythmias, thus necessitating several high-risk reoperations throughout patients' lives. In this study, we evaluated the capacity of mesenchymal stem cells (MSCs) derived from the Wharton's Jelly (WJ-MSCs), the gelatinous inner portion of the umbilical cord, to grow and recellularize an extracellular matrix (ECM) graft in our optimized xeno-free, good manufacturing practice-compliant culture system. WJ-MSCs were phenotypically and functionally characterized by flow cytometry and multilineage differentiation capacity, respectively. The typical MSC immunophenotype and functional characteristics were retained in our xeno-free culture system, as well as the capacity to grow and engraft onto a naturally occurring scaffold. WJ-MSCs, from both human and swine source, showed excellent capacity to recellularize ECM graft producing a living cell-seeded construct. In addition, we have provided an in vivo proof of concept of feasibility of the cellularized conduit, engineered with swine WJ-MSCs, to be used in a novel porcine model of main pulmonary artery reconstruction, where it showed good integration within the host tissue. Our study indicates that the addition of WJ-MSCs to the ECM scaffold can upgrade the material, converting it into a living tissue, with the potential to grow, repair, and remodel the RVOT. These results could potentially represent a paradigm shift in pediatric cardiac intervention toward new modalities for effective and personalized surgical restoration of pulmonary artery and RVOT function in TOF/pulmonary atresia patients. Impact Statement The materials available for pulmonary artery reconstruction in pediatric patients with Congenital Heart Defect come with the limitation of long-term degeneration and lack of growth, thus necessitating several reoperations. Here, we describe a novel approach combining perinatal stem cells and naturally occurring scaffold to create a living tissue engineered conduit that showed good growth potential in a pulmonary artery reconstruction porcine model. We envision this approach is of great interest and relevance in tissue engineering field applied to cardiovascular regenerative medicine, as it may open up new avenues for correction of congenital cardiac defects, with remarkable medical and social benefits.

Rapid Prototyping Flexible Aortic Models Aids Sizing of Valve Leaflets and Planning the Ozaki Repair.

Two patients with bicuspid aortic valve were selected for aortic valve repair using the Ozaki procedure. Patient-specific models of their aortic roots were generated based on computed tomography data and were 3-dimensional printed using a flexible resin. The models allowed sizing of the valve leaflets and practicing of leaflet suturing. (Level of Difficulty: Advanced.).

Combined Degenerative Mitral Valve and Coronary Surgery: Early Outcomes and 10-Year Survival.

BACKGROUND: This study investigated the impact of combined degenerative mitral valve (DMV) and coronary artery bypass grafting (CABG+DMV) surgery vs DMV surgery only on in-hospital health outcome and 10-year survival. METHODS: We identified 745 patients with DMV disease. Of these, 186 (24.9%) were affected also by coronary disease and underwent combined DMV+CABG. They were compared with the remaining 559 patients receiving DMV-only surgery in in-hospital and 1-, 5-, and 10-year survival. We evaluated a short-term composite outcome of hospital mortality, acute kidney injury, cerebrovascular events, and low cardiac output requiring postoperative use of intraaortic balloon pump. In addition, we assessed mitral valve repair rates over time and their correlation with long-term survival. To minimize bias, we conducted a propensity score-matching analysis. RESULTS: DMV+CABG surgery was associated with a similar incidence of the composite end point compared with DMV-only surgery in the unmatched analysis (6.5% vs 5.4%, P = .71) and matched analysis (7.5% vs 8.2%, P = .82). The 10-year survival was 70.5% vs 68.6% (P = .07) for the unmatched analysis and 64.6% vs 62.5% (P = .9) for the matched analysis, DMV+CABG vs DMV-only, respectively. Mitral valve repair had a beneficial effect on short-term outcomes and long-term mortality rates, regardless the presence of concomitant coronary surgery. CONCLUSIONS: Combined DMV+CABG surgery is a very effective surgical treatment with high mitral valve repair rate. Early in-hospital outcome and long-term survival are comparable with DMV-only surgery. In these combined procedures, mitral valve repair is associated with better long-term survival.

Long-Term Comparison Between Pulmonary Homograft Versus Bioprosthesis for Pulmonary Valve Replacement in Tetralogy of Fallot.

Background Tetralogy of Fallot repair results in late occurrence of pulmonary regurgitation, which requires pulmonary valve replacement in a large proportion of patients. Both homografts and bioprostheses are used for pulmonary valve replacement as uncertainty remains on which prosthesis should be considered superior. We performed a long-term imaging and clinical comparison between these 2 strategies. Methods and Results We compared echocardiographic and clinical follow-up data of 209 patients with previous tetralogy of Fallot repair who underwent pulmonary valve replacement with homograft (n=75) or bioprosthesis (n=134) between 1995 and 2018 at a tertiary hospital. The primary end point was the composite of pulmonary valve replacement reintervention and structural valve deterioration, defined as a transpulmonary pressure decrease ≥50 mm Hg or pulmonary regurgitation degree of ≥2. Mixed linear model and Cox regression model were used for comparisons. Echocardiographic follow-up duration was longer in the homograft group (8 [interquartile range, 4-12] versus 4 [interquartile range, 3-6] years; P<0.001). At the latest echocardiographic follow-up, homografts showed a significantly lower transpulmonary systolic pressure decrease (16 [interquartile range, 12-25] mm Hg) when compared with bioprostheses (28 [interquartile range, 18-41] mm Hg; mixed model P<0.001) and a similar degree of pulmonary regurgitation (degree 0-4) (1 [interquartile range, 0-2] versus 2 [interquartile range, 0-2]; mixed model P=0.19). At 9 years, freedom from structural valve deterioration and reintervention was 81.6% (95% CI, 71.5%-91.6%) versus 43.4% (95% CI, 23.6%-63.2%) in the homograft and bioprosthesis groups, respectively (adjusted hazard ratio, 0.27; 95% CI, 0.13-0.55; P<0.001). Conclusions When compared with bioprostheses, pulmonary homografts were associated lower transvalvular gradient during follow-up and were associated with a significantly lower risk of reintervention or structural valve degeneration.

Impact of Body Mass Index on Short- and Long-Term Outcomes After Isolated First-Time Surgical Aortic Valve Replacement for Aortic Stenosis.

OBJECTIVE: To ascertain whether body mass index (BMI) has a clinical effect on short- and long-term postoperative outcomes after surgical aortic valve replacement in patients with severe aortic stenosis. DESIGN: Single-center, retrospective study. SETTING: Tertiary referral hospital. PARTICIPANTS: The study comprised 1,561 patients who underwent isolated first-time aortic valve replacement between 2005 and 2012. INTERVENTIONS: Fourteen underweight patients were removed from the analysis. The remaining patients were divided into the following 4 groups according to their BMI: 418 as normal weight (≥18.5 to <25 kg/m2), 629 as overweight (≥25 to <30 kg/m2), 342 as obese (≥30 to <35 kg/m2), and 158 as very obese (≥35 kg/m2). Early mortality and postoperative complications were compared, and long-term survival rates were investigated. MEASUREMENT AND MAIN RESULTS: Thirty-day mortality was higher in the normal weight group but did not reach statistical significance (p = 0.054), and the incidence of postoperative complications was not different for cerebrovascular accident (p = 0.70), re-sternotomy for bleeding (p = 0.17), sternal wound infection (p = 0.07), and dialysis (p = 0.07). With a mean follow-up time of 4.92 ± 2.82 years, survival rate was better in the overweight group. A Cox proportional hazard model found BMI inversely correlated with long-term mortality when analyzed in a univariable fashion (hazard ratio 0.95; p = 0.009), but this apparent protective effect disappeared when adjusted for preoperative covariates (hazard ratio 0.98, 95% confidence interval 0.96-1.004; p = 0.12). CONCLUSION: Once adjusted for preoperative characteristics, obesity does not represent an independent predictor for long-term survival rates. There was a higher incidence of 30-day mortality in the normal weight group compared with the overweight and very obese groups. The incidence of deep sternal wound infection was higher in very obese patients.

Impact of body mass index on outcomes following mitral surgery: does an obesity paradox exist?

OBJECTIVES: This study was conducted to clarify the relationship between body mass index and mitral valve (MV) surgery and to determine whether an 'obesity paradox' exists in the context of surgery for degenerative MV disease. METHODS: In this retrospective single-centre study, we analysed data from 715 patients who underwent mitral surgery for degenerative disease from 2000 to 2015. Patients were classified according to body mass index: underweight (<20 kg/m2), normal weight (20-24.99 kg/m2), overweight (25-29.99 kg/m2) and obese (≥30 kg/m2). Early and long-term results were investigated. Multivariable analysis was conducted to identify risk factors for long-term mortality. RESULTS: Mean follow-up was 67 ± 44 months (range 0-190 months). There were no differences between groups regarding 30-day mortality (P = 0.35), stroke (P = 0.45), reoperation for bleeding (P = 0.9) and length of hospital stay (P = 0.31). Obese patients were at increased risk of acute kidney injury when compared with normal weight patients (17% vs 5%; P = 0.03) but not when compared with the other groups; this was confirmed within the subgroup with depressed ejection fraction (42% vs 10%, P = 0.02). No differences in long-term survival were found across groups for all patients (P = 0.62) and for patients with depressed ejection fraction (P = 0.6), with a trend towards worse survival in obese patients undergoing MV repair (P = 0.06). Survival in obese patients undergoing repair was significantly worse than that in obese patients undergoing replacement (P = 0.04). CONCLUSIONS: An 'obesity paradox' was not demonstrated after surgery for degenerative MV disease. Obese patients are more prone to acute kidney injury and have worse late survival after MV repair.