Animal models for partial heart transplantation.

BACKGROUND: Partial heart transplantation delivers growing heart valve implants by transplanting the part of the heart containing the necessary heart valve only. In contrast to heart transplantation, partial heart transplantation spares the native ventricles. This has important implications for partial heart transplant biology, including the allowable ischemia time, optimal graft preservation, primary graft dysfunction, immune rejection, and optimal immunosuppression. AIMS: Exploration of partial heart transplant biology will depend on suitable animal models. Here we review our experience with partial heart transplantation in rodents, piglets, and non-human primates. MATERIALS & METHODS: This review is based on our experience with partial heart transplantation using over 100 rodents, over 50 piglets and one baboon. RESULTS: Suitable animal models for partial heart transplantation include rodent heterotopic partial heart transplantation, piglet orthotopic partial heart transplantation, and non-human primate partial heart xenotransplantation. DISCUSSION: Rodent models are relatively cheap and offer extensive availability of research tools. However, rodent open-heart surgery is technically not feasible. This limits rodents to heterotopic partial heart transplant models. Piglets are comparable in size to children. This allows for open-heart surgery using clinical grade equipment for orthoptic partial heart transplantation. Piglets also grow rapidly, which is useful for studying partial heart transplant growth. Finally, nonhuman primates are immunologically most closely related to humans. Therefore, nonhuman primates are most suitable for studying partial heart transplant immunobiology and xenotransplantation. CONCLUSIONS: Animal research is a privilege that is contingent on utilitarian ethics and the 3R principles of replacement, reduction and refinement. This privilege allows the research community to seek fundamental knowledge about partial heart transplantation, and to apply this knowledge to enhance the health of children who require partial heart transplants.

Semilunar valve growth and function 10 years after infant heart transplantation: Predicting long-term outcomes of partial heart transplants.

INTRODUCTION: Partial heart transplants are a new type of pediatric transplant that replace defective heart valves with the parts of matched donor hearts containing the necessary valves. Short-term outcomes of partial heart transplants are excellent, but long-term outcomes are unknown. In order to predict the long-term outcomes of partial heart transplants, we evaluated long-term growth and function of semilunar heart valves transplanted in infancy as part of a heart transplant. METHODS: All children who underwent infant heart transplantation at a single center from 1997 to 2014 were included in this study. Children in whom echocardiograms after heart transplantation and after 10 years were not available for review were excluded. The echocardiograms were reviewed by two authors to analyze semilunar valve annulus diameters, Z-scores, peak valve gradients, and valve regurgitation. Statistical difference was determined using two-tailed, paired sample t-tests with Bonferroni correction for multiple comparisons. RESULTS: Data from 15 patients were analyzed. The aortic valve annulus averaged 1.3 cm (range 0.7-1.8 cm) immediately after transplantation and grew to an average of 1.7 cm (range 1.4-2.3 cm) after 10 years (p < .001). After 10 years, the aortic valve peak gradient avereraged 5.1 mmHg (range 2.1-15.5 mmHg) and none of the valves had more than trivial regurgitation. The pulmonary valve annulus averaged 1.5 cm (range 1.1-2.5 cm) immediately after transplantation and grew to an average of 2.1 cm (range 1.0-2.9 cm) after 10 years (p < .001). After 10 years, the pulmonary valve peak gradient averaged 4.3 mmHg (range 1.1-13.8 mmHg), and 7% of valves had moderate regurgitation. DISCUSSION: Semilunar heart valves transplanted in infancy as part of a heart transplant demonstrate statistically significant growth and excellent function after 10 years. This predicts excellent long-term outcomes of partial heart transplants.

Partial Heart Transplantation - How to Change the System.

Partial heart transplantation is the first clinically successful approach to deliver growing heart valve implants. To date, 13 clinical partial heart transplants have been performed. However, turning partial heart transplantation into a routine procedure that is available to all children who would benefit from growing heart valve implants poses formidable logistical challenges. Firstly, a supply for partial heart transplant donor grafts needs to be developed. This challenge is complicated by the scarcity of donor organs. Importantly, the donor pools for orthotopic heart transplants, partial heart transplants and cadaver homografts overlap. Secondly, partial heart transplants need to be allocated. Factors relevant for equitable allocation include the indication, anatomical fit, recipient clinical status and time on the wait list. Finally, partial heart transplantation will require regulation and oversight, which only recently has been undertaken by the Food and Drug Administration, which regulates human cellular and tissue-based products. Overcoming these challenges will require a change in the system. Once this is achieved, partial heart transplantation could open new horizons for children who require growing tissue implants.

Partial Heart Transplant in a Neonate With Irreparable Truncal Valve Dysfunction.

Importance: The treatment of neonates with irreparable heart valve dysfunction remains an unsolved problem because there are no heart valve implants that grow. Therefore, neonates with heart valve implants are committed to recurrent implant exchanges until an adult-sized valve can fit. Objective: To deliver the first heart valve implant that grows. Design, Setting, and Participants: Case report from a pediatric referral center, with follow-up for more than 1 year. Participants were a recipient neonate with persistent truncus arteriosus and irreparable truncal valve dysfunction and a donor neonate with hypoxic-ischemic brain injury. Intervention: First-in-human transplant of the part of the heart containing the aortic and pulmonary valves. Main Outcomes and Measures: Transplanted valve growth and hemodynamic function. Results: Echocardiography demonstrated adaptive growth and excellent hemodynamic function of the partial heart transplant valves. Conclusions and Relevance: In this child, partial heart transplant delivered growing heart valve implants with a good outcome at age 1 year. Partial heart transplants may improve the treatment of neonates with irreparable heart valve dysfunction.

Extremity tourniquets raise blood pressure and maintain heart rate.

BACKGROUND: Tourniquets have been modified and used for centuries to occlude blood flow to control hemorrhage. More recently, the occlusion of peripheral vessels has been linked to resultant increases in blood pressure, which may provide additional therapeutic potential, particularly during states of low cardiac output. OBJECTIVE: The objective of this study was to investigate a causal relationship between tourniquet application and blood pressure in healthy adults. METHODS: Healthy adult volunteers were recruited to participate in this IRB-approved study. Each participant met inclusion criteria and demonstrated baseline normotension. Brachial cuff blood pressure and heart rate were recorded pre- and post-tourniquet application to the bilateral legs. RESULTS: Twenty-seven adults aged 22 to 35 years participated and were included in analysis. The average systolic blood pressure was 122 ± 7 mmHg, diastolic blood pressure was 72 ± 9 mmHg, and heart rate was 70 ± 13 bpm. Following bilateral tourniquet application over the femoral vasculature, we observed a statistically significant increase in systolic (7 mmHg, p < 0.001) and diastolic (4 mmHg, p = 0.05) blood pressures with no significant change in heart rate (2 bpm, p > 0.05). CONCLUSIONS: The elevations in systolic and diastolic blood pressures establish a dependent relationship between tourniquet application to the lower extremities and blood pressure elevation. These results may support new indications for tourniquet-use or extremity vessel occlusion in settings of hemodynamic instability.

Partial heart transplantation can ameliorate donor organ utilization.

BACKGROUND: The treatment of babies with unrepairable heart valve dysfunction remains an unsolved problem because there are no growing heart valve implants. However, orthotopic heart transplants are known to grow with recipients. AIM: Partial heart transplantation is a new approach to delivering growing heart valve implants, which involves transplantation of the part of the heart containing the valves only. In this review, we discuss the benefits of this procedure in children with unrepairable valve dysfunction. CONCLUSION: Partial heart transplantation can be performed using donor hearts with poor ventricular function and slow progression to donation after cardiac death. This should ameliorate donor heart utilization and avoid both primary orthotopic heart transplantation in children with unrepairable heart valve dysfunction and progression of these children to end-stage heart failure.

Recipient-surgeon racial concordance in orthotopic heart transplantation outcomes.

BACKGROUND: Prior studies have demonstrated deleterious outcomes for physician-patient racial discordance. We explored recipient-surgeon racial concordance and short-term postoperative survival in adults undergoing orthotopic heart transplantation (OHT). METHODS: The United Network for Organ Sharing (UNOS) database was queried to identify White and Black adult (≥18 years) patients undergoing isolated OHT between 2000 and 2020. Surgeon race was obtained from publicly available images. All non-White and non-Black recipients and surgeons were excluded. Linear probability models were utilized to explore the relationship between recipient-surgeon racial concordance and 30-, 60-, and 90-day post-transplant mortality using a fixed effects approach. RESULTS: A total of 26,133 recipients were identified (mean age 52.79 years, 74.4% male) with 77.65% (n = 20,292) being White and 22.35% (n = 5841) being Black. A total of 662 White surgeons performed 25,946 (97.56%) OHTs during the study period while 17 Black surgeons performed 437 (1.67%) OHTs. Although some evidence of differences across groups was observed in cross-tabular specifications, these differences became insignificant after the inclusion of controls (i.e., comorbidities and fixed effects). This suggests that recipient race and physician race are not correlated with post-OHT survival at 30, 60, or 90 days. CONCLUSIONS: Recipient-surgeon racial concordance and discordance among adults undergoing OHT do not appear to impact post-transplant survival. Nor do we observe significant penalties accruing for Black patients overall once controls are accounted for. Given that worse outcomes have historically been demonstrated for Black patients undergoing OHT, further work will be necessary to improve understanding of racial disparities for patients with end-stage heart failure.

Adhesion barriers in cardiac surgery: A systematic review of efficacy.

BACKGROUND: Postoperative pericardial adhesions have been associated with increased morbidity, mortality, and surgical difficulty. Barriers exist to limit adhesion formation, yet little is known about their use in cardiac surgery. The study presented here provides the first major systematic review of adhesion barriers in cardiac surgery. METHODS: Scopus and PubMed were assessed on November 20, 2020. Inclusion criteria were clinical studies on human subjects, and exclusion criteria were studies not published in English and case reports. Risk of bias was evaluated with the Cochrane Risk of Bias Tool. Barrier efficacy data was assessed with Excel and GraphPad Prism 5. RESULTS: Twenty-five studies were identified with a total of 13 barriers and 2928 patients. Polytetrafluoroethylene (PTFE) was the most frequently evaluated barrier (13 studies, 67% of patients) with adhesion formation rate of 37.31% and standardized tenacity score of 26.50. Several barriers had improved efficacy. In particular, Cova CARD had a standardized tenacity score of 15.00. CONCLUSIONS: Overall, the data varied considerably in terms of study design and reporting bias. The amount of data was also limited for the non-PTFE studies. PTFE has historically been effective in preventing adhesions. More recent barriers may be superior, yet the current data is nonconfirmatory. No ideal adhesion barrier currently exists, and future barriers must focus on the requirements unique to operating in and around the heart.

Expression of CD68 positive macrophages in the use of different barrier materials to prevent peritoneal adhesions-an animal study.

In preventing postoperative adhesion formation the optimal barrier material has still not been found. It is therefore imperative to assess the biocompatibility of potential barrier devices. Macrophages play a decisive role in the regulation of wound healing, tissue regeneration and foreign body reaction. Since the number of CD68-positive macrophages represents an important parameter within biomaterial testing, in the present study it was analysed whether a correlation exists between the total number of CD68-positive macrophages and the extent of fibrosis or inflammation in peritoneal adhesion prevention using biomaterials. After standardized peritoneal wounding, Wistar rats were treated with five adhesion barriers or remained untreated as a control. After 14 days, animals were sacrificed and the treated areas were evaluated histomorphologically and immunohistologically. A heterogeneous pattern of macrophage count in relation to fibrosis or inflammation was found. While some groups described a moderate macrophage infiltration without fibrosis, others showed similar numbers of macrophages, but accompanied by moderate fibrosis. Moreover, a minimal number of macrophages was associated with minimal fibrosis. Mild inflammation was seen both with minimal and moderate macrophage infiltration. Altogether, no correlation could be established between the tissue response and the count of CD68-positive macrophages. With a view to macrophage heterogeneity further studies are required to determine the different macrophage subpopulations and clarify the role of these in the tissue responses to barrier materials.

Intraoperative thermographic imaging to assess myocardial distribution of Del Nido cardioplegia.

We describe the intraoperative non-invasive use of an infrared (IR) camera to monitor Del Nido cardioplegia delivery in patients undergoing cardiac surgery. Thermal pictures were taken pre- and post-cardioplegia and at timed points after arrest, and compared to readings from a transseptal temperature probe. There was good concordance between the transseptal probe and the IR camera temperature readings. This non-invasive technique, which assesses cardioplegic distribution, may help to determine when additional doses of Del Nido cardioplegia are required during periods of cardioplegic arrest.

Impact of increasing operative time on the incidence of early failure and complications following free tissue transfer? A risk factor analysis of 2,008 patients from the ACS-NSQIP database.

BACKGROUND: There is a scarcity of externally valid data that investigate the utility of operative time, a common clinical parameter, as a predictor of free flap failures. Our aim was to assess whether prolonged operative time correlates with early flap failure following free tissue transfer in the acute care setting using the American College of Surgeons National Surgical Quality Improvement Program database. METHODS: The 2005-2011 American College of Surgeons National Surgical Quality Improvement Program databases were reviewed for encounters that entailed a free tissue transfer via a CPT algorithm. Patients identified as having a flap loss were compared with people who did not with regards to operative time and patient comorbidities. Patients were subdivided into the following cohort groups with regards to operative time: <6 hours, 6-12 hours, and >12 hours. Secondary outcome was association between increasing operative time and postoperative complications. RESULTS: Of the 2,008 patients identified, 62 (3.1%) had early flap failure. After multivariable analysis, it was found that progressive operative time was associated with an increased risk of flap failure; 6-12 hours odds ratio was 4.64 and >12 hours odds ratio was 5.65 (P = 0.0140). Higher American Society of Anesthesiologists class (P = 0.0042) was also shown to be significantly associated with flap failure. On secondary analysis, increasing operative time was correlated with the following complications: pneumonia, blood transfusions, prolonged ventilation, wound dehiscence, and wound complications. CONCLUSION: Our results, one of the largest series in the literature, revealed that prolonged operative time was associated with a stepwise increase in the likelihood of early flap failure as well certain postoperative complications. © 2014 Wiley Periodicals, Inc. Microsurgery 37:12-20, 2017.

The future of partial heart transplantation.

Heart valve replacement in children is an unsolved problem in congenital cardiac surgery because state-of-the-art heart valve implants do not grow. This leads to serial repeat operations to replace outgrown heart valve implants. Partial heart transplantation is a new transplant that helps alleviate this problem by delivering growing heart valve implants. In the future, partial heart transplantation has the potential to complement conventional heart transplantation for treating children with congenital cardiac disease primarily affecting the heart valves.

Microaxial mechanical circulatory support after orthotopic heart transplantation.

AIM: Use of microaxial mechanical circulatory support (MCS) has been reported for severe graft rejection or dysfunction after heart transplantation (HTx). We aimed to assess utilization patterns of microaxial MCS after HTx in adolescents (ages 18 and younger) and adults (ages 19 and older). METHODS: Electronic search was performed to identify all relevant studies on post-HTx use of microaxial support in adults and adolescents. A total of 18 studies were selected and patient-level data were extracted for statistical analysis. RESULTS: All patients (n=23), including adults (n=15) and adolescents (n=8), underwent Impella (Abiomed, Danvers, MA) microaxial MCS after HTx. Median age was 36 [IQR 18-56] years (Adults, 52 [37-59]; adolescents, 16 [15-17]). Primary right ventricular graft dysfunction was an indication exclusively seen in the adults 40% (6/15), while acute graft rejection was present in 46.7% (7/15) of adults. Median time after transplant was 9 [0-32] months (Adults, 4 [0-32]; adolescents, 11 [4.5, 45]). Duration of Impella support was comparable between adults and adolescents (5 [2.5-8] vs 6 [5-8] days, p = 0.38). Overall improvement was observed both in median LV ejection fraction (23.5% [11.3-28] to 42% [37.8-47.3], p < 0.01) and cardiac index (1.8 [1.2-2.6] to 3 [2.5-3.1], p < 0.01). Retransplantation was required in four adolescents (50%, 4/8). Survival to discharge was achieved by 60.0% (9/15) of adults and 87.5% (7/8) of adolescents respectively (p = 0.37). CONCLUSION: Indications for microaxial MCS appear to vary between adult and adolescent patients. Overall improvement in LVEF and cardiac index was observed, however, with suboptimal survival to discharge.

A single-center, nonblinded, clinical trial comparing blood pressures before and after tourniquet application in healthy humans: A study protocol.

INTRODUCTION: Cardiac arrest is the leading cause of natural death in the United States, and most surviving patients suffer from neurological dysfunction. Although this is recognized as a problem, there have been very few changes to the cardiopulmonary resuscitation (CPR) procedure. Tourniquets have been recognized for their ability to increase truncal blood pressure and have been shown to improve CPR outcomes in animal models. However, the relationship between tourniquet application and blood pressure elevation has not been adequately explored in healthy human adults. OBJECTIVES: The objective of this study is to demonstrate that bilateral, non-invasive, peripheral vascular occlusion in the thighs results in an increased proximal systolic blood pressure ≥ 10 mmHg. METHODS: This is a single-center, non-blinded clinical trial. Volunteers will be screened for eligibility at least 24 hours before the day of the trial. On the day of the trial, volunteers will undergo an informed consent process. If they choose to participate in the trial after informed consent, their baseline blood pressure will be measured. Volunteers will then have a Combat Application Tourniquet (CAT) applied to each thigh, and the windlasses will be tightened by IRB-approved personnel. Once no pulse can be felt in the lower extremity, blood pressure will be measured in the arm. This will be replicated three times, and the tourniquets will be loosened between trials to allow the volunteers to rest. Any complications that arise during the trial will be handled by the physician that is present. ANALYSIS: Changes in systolic blood pressure and diastolic blood pressure will be analyzed using a Shapiro-Wilk test. Then, a one-way repeated measures analysis of variance (ANOVA) will be performed with a Holm-Sidak post-hoc test to determine the mean differences. The significance level will be set to 5% for statistical significance. REGISTRY AND REGISTRATION NUMBER: Clinicaltrials.gov, NCT05324306.

Partial Heart Transplantation in Adult Cardiac Surgery.

Many young adults require heart valve replacements. Current options for valve replacement in adults include mechanical valves, bioprosthetic valves, or the Ross procedure. Of these, mechanical and bioprosthetic valves are the most common options, although mechanical valve usage predominates in younger adults due to durability, while bioprosthetic valve usage predominates in older adults. Partial heart transplantation is a new method of valvular replacement that can deliver durable and self-repairing valves and allow adult patients freedom from anticoagulation therapy. This procedure involves transplantation of donor heart valves only, permitting expanded utilization of donor hearts as compared with orthotopic heart transplantation. In this review, we discuss the potential benefits of this procedure in adults who elect against the anticoagulation regimen required of mechanical valve replacements, although it has not yet been clinically established. Partial heart transplantation is a promising new therapy for the treatment of pediatric valvular dysfunction. This is a novel technique in the adult population with potential utility for valve replacement in young patients for whom anticoagulation therapy is problematic, such as women who wish to become pregnant, patients with bleeding disorders, and patients with active lifestyles.

Growing Heart Valve Implants for Children.

The current standard of care for pediatric patients with unrepairable congenital valvular disease is a heart valve implant. However, current heart valve implants are unable to accommodate the somatic growth of the recipient, preventing long-term clinical success in these patients. Therefore, there is an urgent need for a growing heart valve implant for children. This article reviews recent studies investigating tissue-engineered heart valves and partial heart transplantation as potential growing heart valve implants in large animal and clinical translational research. In vitro and in situ designs of tissue engineered heart valves are discussed, as well as the barriers to clinical translation.