Performance of allogeneic bioengineered replacement pulmonary valves in rapidly growing young lambs.

BACKGROUND: Cardiac allometric organ growth after pediatric valve replacement can lead to patient-prosthesis size mismatch and valve re-replacement, which could be mitigated with allogeneic decellularized pulmonary valves treated with collagen conditioning solutions to enhance biological and mechanical performance, termed "bioengineered valves." In this study, we evaluated functional, dimensional, and biological responses of these bioengineered valves compared with traditional cryopreserved valves implanted in lambs during rapid somatic growth. METHODS: From a consanguineous flock of 13 lambs, the pulmonary valves of 10 lambs (mean weight, 19.6 ± 1.4 kg) were replaced with 7 bioengineered valves or 3 classically cryopreserved valves. After 6 months, the 10 lambs with implanted valves and 3 untreated flock mates were compared by echocardiography, cardiac catheterization, and explant pathology. RESULTS: Increases in body mass, valve geometric dimensions, and effective orifice areas were similar in the 2 groups of lambs. The bioengineered valves had higher median cusp-to-cusp coaptation areas (34.6%; interquartile range, 21.00%-35.13%) and were more similar to native valves (43.4%; interquartile range, 42.59%-44.01%) compared with cryopreserved valves (13.2%; interquartile range, 7.07%-13.91%) (P = .043). Cryopreserved valves cusps, but not bioengineered valve cusps, were thicker than native valve cusps (P = .01). Histologically, cryopreserved valves demonstrated less than native cellularity, whereas bioengineered valves that were acellular at the time of surgery gained surface endothelium and subsurface myofibroblast interstitial cells in pulmonary artery, sinus wall, and cusp base regions. CONCLUSIONS: Biological valve conduits can enlarge via passive dilatation without matrix synthesis, but this would result in decreased cusp coaptational areas. Bioengineered valves demonstrated similar annulus enlargement as cryopreserved valves but usually retained larger areas of cuspal coaptation. Heat-shock protein 47-positive (collagen-synthesizing) cells were present in previously acellular bioengineered sinus walls and cusp bases, but rarely in more distal cusp matrices.

Long-term survival after use of internal thoracic artery in octogenarians is gender related.

OBJECTIVE: The goal of this study is to assess the benefits of a left internal thoracic artery as a bypass conduit in octogenarians undergoing elective coronary artery bypass grafting. We hypothesize that there is no survival advantage and that outcome may be gender related. METHODS: In a retrospective analysis of 1141 octogenarians (aged >80 years) undergoing isolated coronary artery bypass grafting from 1996 to 2012, patients were divided into 2 groups: Group I (coronary artery bypass grafting-left internal thoracic artery) included 870 patients (339 female/531 male), and group II (coronary artery bypass grafting-saphenous vein graft) included 271 patients (131 female/140 male). RESULTS: The overall 30-day mortality was 5.7%: 4.3% in group I and 7.0% in group II (P = .1). Group II had a lower trend of any postoperative complication (P = .05) and pneumonia (P = .05). When analyzed by gender, there were no discernable differences in long-term survival for male patients in group I (65% at 5 years and 29% at 10 years) versus male patients in group II (65% at 5 years and 31% at 10 years) (P = .2). However, survival was significantly greater for female patients in group I (70% at 5 years and 35% at 10 years) versus female patients in group II (63% at 5 years and 21% at 19 years) (P = .01). Multiple logistic and Cox regression analysis showed that left internal thoracic artery use is associated with improved survival in female patients (hazard ratio [HR], 0.72; confidence interval [CI], 0.56-0.93) but not in male patients (HR, 1.14; CI, 0.9-1.4). Advanced age was associated with an increased risk of mortality (HR, 1.08 per year; CI, 1.05-1.1). Both patient age (P = .01) and Society of Thoracic Surgeons-predicted 30-day mortality (P = .03) remain in the final model for 30-day mortality. The benefit of the left internal thoracic artery after coronary artery bypass grafting in octogenarians may be gender related. CONCLUSIONS: This study shows that the benefit of the left internal thoracic artery in the octogenarian population undergoing coronary artery bypass grafting may be gender related. For elderly female patients, the use of the left internal thoracic artery as a bypass conduit was associated with better long-term survival, whereas no significant difference was found among the male population. The use of the left internal thoracic artery was associated with a greater postoperative pulmonary morbidity for the study population as a whole. The present study does not refute the benefit of the left internal thoracic artery-left anterior descending graft, but instead distinguishes a subset who might benefit more.

Bioengineered human and allogeneic pulmonary valve conduits chronically implanted orthotopically in baboons: hemodynamic performance and immunologic consequences.

OBJECTIVE: This study assesses in a baboon model the hemodynamics and human leukocyte antigen immunogenicity of chronically implanted bioengineered (decellularized with collagen conditioning treatments) human and baboon heart valve scaffolds. METHODS: Fourteen baboons underwent pulmonary valve replacement, 8 with decellularized and conditioned (bioengineered) pulmonary valves derived from allogeneic (N = 3) or xenogeneic (human) (N = 5) hearts; for comparison, 6 baboons received clinically relevant reference cryopreserved or porcine valved conduits. Panel-reactive serum antibodies (human leukocyte antigen class I and II), complement fixing antibodies (C1q binding), and C-reactive protein titers were measured serially until elective sacrifice at 10 or 26 weeks. Serial transesophageal echocardiograms measured valve function and geometry. Differences were analyzed with Kruskal-Wallis and Wilcoxon rank-sum tests. RESULTS: All animals survived and thrived, exhibiting excellent immediate implanted valve function by transesophageal echocardiograms. Over time, reference valves developed a smaller effective orifice area index (median, 0.84 cm(2)/m(2); range, 1.22 cm(2)/m(2)), whereas all bioengineered valves remained normal (effective orifice area index median, 2.45 cm(2)/m(2); range, 1.35 cm(2)/m(2); P = .005). None of the bioengineered valves developed elevated peak transvalvular gradients: 5.5 (6.0) mm Hg versus 12.5 (23.0) mm Hg (P = .003). Cryopreserved valves provoked the most intense antibody responses. Two of 5 human bioengineered and 2 of 3 baboon bioengineered valves did not provoke any class I antibodies. Bioengineered human (but not baboon) scaffolds provoked class II antibodies. C1q(+) antibodies developed in 4 recipients. CONCLUSIONS: Valve dysfunction correlated with markers for more intense inflammatory provocation. The tested bioengineering methods reduced antigenicity of both human and baboon valves. Bioengineered replacement valves from both species were hemodynamically equivalent to native valves.

Transesophageal Echocardiography in Healthy Young Adult Male Baboons (Papio hamadryas anubis): Normal Cardiac Anatomy and Function in Subhuman Primates Compared to Humans.

Implantable, viable tissue engineered cardiovascular constructs are rapidly approaching clinical translation. Species typically utilized as preclinical large animal models are food stock ungulates for which cross species biological and genomic differences with humans are great. Multiple authorities have recommended developing subhuman primate models for testing regenerative surgical strategies to mitigate xenotransplant inflammation. However, there is a lack of specific quantitative cardiac imaging comparisons between humans and the genomically similar baboons (Papio hamadryas anubis). This study was undertaken to translate to baboons transesophageal echocardiographic functional and dimensional criteria defined as necessary for defining cardiac anatomy and function in the perioperative setting. Seventeen young, healthy baboons (approximately 30 kg, similar to 5 year old children) were studied to determine whether the requisite 11 views and 52 measurement parameters could be reliably acquired by transesophageal echocardiography (TEE). The obtained measurements were compared to human adult normative literature values and to a large relational database of pediatric "normal heart" echo measurements. Comparisons to humans, when normalized to BSA, revealed a trend in baboons toward larger mitral and aortic valve effective orifice areas and much larger left ventricular muscle mass and wall thickness, but similar pulmonary and tricuspid valves. By modifying probe positioning relative to human techniques, all recommended TEE views except transgastric could be replicated. To supplement, two transthoracic apical views were discovered that in baboons could reliably replace the transgastric TEE view. Thus, all requisite echo views could be obtained for a complete cardiac evaluation in Papio hamadryas anubis to noninvasively quantify cardiac structural anatomy, physiology, and dimensions. Despite similarities between the species, there are subtle and important physiologic and anatomic differences when compared to human.

Performance and morphology of decellularized pulmonary valves implanted in juvenile sheep.

BACKGROUND: Because of cryopreserved heart valve-mediated immune responses, decellularized allograft valves are an attractive option in children and young adults. The objective of this study was to investigate the performance and morphologic features of decellularized pulmonary valves implanted in the right ventricular outflow tract of juvenile sheep. METHODS: Right ventricular outflow tract reconstructions in juvenile sheep (160±9 days) using cryopreserved pulmonary allografts (n=6), porcine aortic root bioprostheses (n=4), or detergent/enzyme-decellularized pulmonary allografts (n=8) were performed. Valve performance (echocardiography) and morphologic features (gross, radiographic, and histologic examination) were evaluated 20 weeks after implantation. RESULTS: Decellularization reduced DNA in valve cusps by 99.3%. Bioprosthetic valves had the largest peak and mean gradients versus decellularized valves (p=0.03; p<0.001) and cryopreserved valves (p=0.01; p=0.001), which were similar (p=0.45; p=0.40). Regurgitation was minimal and similar for all groups (p=0.16). No cusp calcification was observed in any valve type. Arterial wall calcification was present in cryopreserved and bioprosthetic grafts but not in decellularized valves. No autologous recellularization or inflammation occurred in bioprostheses, whereas cellularity progressively decreased in cryopreserved grafts. Autologous recellularization was present in decellularized arterial walls and variably extending into the cusps. CONCLUSIONS: Cryopreserved and decellularized graft hemodynamic performance was comparable. Autologous recellularization of the decellularized pulmonary arterial wall was consistently observed, with variable cusp recellularization. As demonstrated in this study, decellularized allograft valves have the potential for autologous recellularization.

Decellularization reduces calcification while improving both durability and 1-year functional results of pulmonary homograft valves in juvenile sheep.

OBJECTIVE: The juvenile sheep functional valve chronic implant calcification model was used to compare long-term calcification rates, functional performance, and durability for 3 types of right ventricular outflow tract implants: classically cryopreserved homografts and 2 decellularized pulmonary valved conduits. METHODS: Fifteen juvenile sheep were randomly assigned to one of 3 study arms and underwent pulmonary valve replacement. The arms included the following: (1) cryopreserved ovine pulmonary valves; (2) cryopreserved, decellularized, saline (1 degrees C-10 degrees C)-stored ovine pulmonary valves; and (3) cryopreserved, decellularized, glycerolized (-80 degrees C) stored ovine pulmonary valves. Animal growth, serial echocardiographic results (with valve performance assessment), dimensions, and tissue-specific calcification measurements were compared with pre-explant angiographic analysis and right ventricular outflow tract pressure measurements, cardiac magnetic resonance imaging, specimen radiographic analysis, gross explant pathology, and histopathology. Parametric and nonparametric statistical analysis were performed. RESULTS: All but 2 study animals receiving implants thrived postoperatively, with similar growth rates, explant valve dimensions, ventricular functions, cardiac output, and indices during the study. As determined by means of echocardiographic analysis, 3 animals in arm 1 (and one in arm 2) had leaflet dysfunction. Valve regurgitation was recognized in 1 survivor each from both arms 1 and 2. Although 1 arm 1 animal died with calcified subacute bacterial endocarditis, and the other 4 had leaflet and conduit wall calcification by the time of death, no arm 2 or arm 3 animals demonstrated leaflet calcium, and no arm 3 and only 1 arm 2 animals had calcium in the conduit wall over the entire year, as determined with any measurement method. All cryopreserved conduit walls had calcium by 20 weeks, whereas only 1 of 10 decellularized conduits (arms 2 plus 3) had wall calcium. CONCLUSION: Cryopreserved-decellularized-glycerolized valves retained normal valve function, with absent leaflet and minimal wall calcifications 1 year postoperatively, as opposed to classically cryopreserved allografts. These results might be predictive of the prolonged durability and functionality of a cryopreserved-decellularized-glycerolized allograft valve.

The influence of cognitive reserve on neuropsychological functioning following coronary artery bypass grafting (CABG).

Neuropsychological impairment is common, yet variable, after coronary artery bypass grafting (CABG). Similar variability has been observed in other CNS-related diseases. Empirical findings in Alzheimer's disease and HIV, among other areas, suggest cognitive reserve (CR) may mediate the cognitive impact of these diseases. The present study examined whether CR mediates neuropsychological outcome after CABG. Participants were 42 (N=42) individuals who underwent elective, normothermic CABG. Each was placed in high (n=22) or low (n=20) CR groups based on estimated premorbid intelligence and occupational attainment. All were administered neuropsychological tests preoperatively and at discharge. The total incidence of neuropsychological decline (66.7%) was not significantly different between CR groups. However, on working memory and executive function tests, specifically, the high CR group demonstrated greater post-operative decline compared to the low CR group. These data are considered in the context of a threshold model of CR theory.

Surgical patch closure of atrial septal defects.

BACKGROUND: Development of nonsurgical techniques for closure of atrial septal defects (ASD) has prompted reevaluation of current surgical outcomes with an emphasis on less invasive methods. METHODS: This retrospective review is based on a single surgeon's experience between July 1, 1988 and December 21, 2002 with 176 consecutive adult (n = 47) and pediatric (n = 129) surgeries, in which ASD was the primary anatomical diagnosis to ascertain current optimal methods and outcomes expected for surgical closure. Patch closure with pericardium was used in all cases. Surgical methods encompassed three phases. The first phase was defined by traditional sternotomy; the second phase involved a series of technical modifications to shorten incisions and reduce surgical trauma; the third phase consisted of standardized less invasive techniques based upon age and gender with "bikini line" incisions for adult females, limited median sternotomy for adult males, and mini-median sternotomy for children. All patients underwent echocardiography to assess ASD closure. RESULTS: There were no deaths. The most frequent perioperative complications were atrial fibrillation (adult 10%, pediatric 1.2%) and post pericardiotomy syndrome (adult 2%, pediatric 4.7%). All patients had secure and complete closure of ASDs with no residual shunts (trivial or otherwise) documented by echocardiography. No less invasive procedures required conversion. CONCLUSIONS: Surgical technique evolved from standard sternotomy to limited access incisions using modified cannulation techniques and incision locations determined by age and gender of the patient without deterioration in outcome quality. Both standard and less invasive surgical methods can achieve secure closure of the septum with biological patches, which are incorporated into the tissue structure of the heart and which are free from materials-related failure modes. Patient satisfaction is enhanced by utilizing the least invasive, least traumatic, and most cosmetically appealing techniques for access and cardiopulmonary bypass.