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Xenotransplant covers a broad ethical territory and there are several ethical questions that have arisen in parallel with the technological advances that have allowed the first porcine transplants to occur. This brief communication highlights ethical considerations regarding heart and lung xenotransplantation, with an emphasis on unresolved value-based concerns in the field. The aim of this text is therefore to encourage the readers to consider the vast potential of this emerging technique to do good, but also the risk of doing harm, and to participate in a discussion. The list of questions presented here is not exhaustive but hopefully represents some of the questions that appear to be most pressing as the field advances. The focus is on the value-based, or ethical questions, not the questions related to the practical medical procedures., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures Angela Velleca None Michael A Shullo Consulting- Natera Kumud Dhital None Estela Azeka MD None Monica Colvin MD Grants- Natera-Grant funding; Advisory board- Natera; Consulting- Mescape Eugene DePasquale Grants- CareDX; Advisory Board- Yale Marta Farrero Speakers bureaus- Novatris, AstraZeneca, Boehringer, Chiesi; Meeting support- Novartis, Chiesi; Material support/ Other Services- AstraZeneca Luis García-Guereta None Gina Jamero None Kiran Khush Grants- National Institutes of Health, Enduring Hearts; Royalties- Stanford; Consulting, speakers bureaus- CareDx Jacob Lavee None Stephanie Pouch None Jignesh Patel Grants- Alexion; Consulting- CareDx, Natera; Advisory Board- CareDx, Natera; CJ Michaud None Stephan Schubert Consulting- Medtronic, Edwards; Speakers Bureaus- Abbott, Lifetech, Medtronic; Meeting support- Medtronic, Edwards Annalisa Angelini None Lilibeth Carlos None Sonia Mirabet None Michael Pham Grants- CareDx, Royalties-Up to Date Simon Urschel Grants- Canadian Institute for Health Research, Enduring Hearts, Heart and Stroke foundation; Speaker/Educational- University of Alabama; Meeting support- Lange Symposium; Advisory Board- SMB of the Canadian Donation and Transplantation Research Program Kyung-Hee Kim None Shelly Miyamoto None Sharon Chih Grants- Heart and Stroke Foundation Ontario, Canadian Institutes of Health Research Kevin Daly Grants- US Department of Defense, Novartis, AHA/Enduring Hearts, Consulting- AstraZeneca; Advisory Board- CareDx Paolo Grossi Consulting- Merck, Sharp & Dohme Allovir, Takeda; Speakers Bureaus- Atara, Gilead, Shionogi; Advisory Board- Reithera Doug Jennings None In-cheol Kim None Hoong Sern Lim Speakers bureaus- Abiomed Tara Miller None Luciano Potena Consulting- Biotest, Novartis; Speakers bureaus- Biotest, Takada, Paragonix, Boeringher Ingheleim, AstraZeneca Howard Eisen None Lavanya Bellumkonda Grants- Natera, CareDx; Meeting support- Conformal Medical; Advisory Board- CareDx Lara Danziger-Isakov Grants- NIH, Ansun BioPharma, Astellas, Merck, Pfizer, Takada, AiCuris; Consulting- Takeda; Speakers Bureaus- RMEI; Meeting support- ID SAFE: Swiss Infectious Disease; Advisory Board/DSMB- Merck Fabienne Dobbels None Michelle Harkess None Daniel Kim None Haifa Lyster None Yael Peled None Zdenka Reinhardt None

Background: The durability of the immune response following the 3-dose BNT162b2 vaccination is unknown. The complexity of the situation is enhanced by the threat that highly transmissible variants may further accelerate the decline in the protection afforded by mRNA vaccines., Methods: One hundred and three 3-dose-vaccinated heart transplant recipients were longitudinally assessed for the kinetics of variant-specific neutralization (Cohort 1, n = 60) and SARS-CoV-2-specific-T-cell response (Cohort 2, n = 54) over 6 months. Neutralization and T-cell responses were compared between paired samples at 2 time points, using the Kruskal-Wallis test followed by Dunn's multiple comparison test for continuous variables and McNemar's test for dichotomous variables. The Bonferroni method of p values adjustment for multiple comparison was applied., Results: The third dose induced high neutralization of the wild-type virus and delta variant (geometric mean titer [GMT], 137.2 [95% CI, 84.8-221.9] and 80.6, [95% CI, 49.3-132.0], respectively), and to a lesser degree of the omicron variant (GMT, 10.3 [95% CI, 5.9-17.9]). At 6 months, serum neutralizing activity declined but was still high for the wild-type virus and for the delta variant (GMTs 38.1 [95% CI, 21.2-69.4], p = 0.011; and 28.9 [95% CI, 16.6-52.3], p = 0.022, respectively), but not for the omicron variant (GMT 5.9 [95% CI, 3.4-9.8], p = 0.463). The percentages of neutralizing sera against the wild-type virus, delta and omicron variants increased from 70%, 65%, and 38%, before the third dose, to 93% (p < 0.001), 88% (p < 0.001), and 48% (p = 0.021) at 3 weeks after, respectively; and remained high through the 6 months for the wild-type (80%, p = 0.06) and delta (77%, p = 0.102). The third dose induced the development of a sustained SARS-CoV-2-specific-T-cell population, which persisted through 6 months., Conclusions: The third BNT162b2 dose elicited a durable SARS-CoV-2-specific T-cell response and induced effective and durable neutralization of the wild-type virus and the delta variant, and to a lesser degree of the omicron variant., Competing Interests: Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The dead donor rule is fundamental to transplant ethics. The rule states that organ procurement must not commence until the donor is both dead and formally pronounced so, and by the same token, that procurement of organs must not cause the death of the donor. In a separate area of medical practice, there has been intense controversy around the participation of physicians in the execution of capital prisoners. These two apparently disparate topics converge in a unique case: the intimate involvement of transplant surgeons in China in the execution of prisoners via the procurement of organs. We use computational text analysis to conduct a forensic review of 2838 papers drawn from a dataset of 124 770 Chinese-language transplant publications. Our algorithm searched for evidence of problematic declarations of brain death during organ procurement. We find evidence in 71 of these reports, spread nationwide, that brain death could not have properly been declared. In these cases, the removal of the heart during organ procurement must have been the proximate cause of the donor's death. Because these organ donors could only have been prisoners, our findings strongly suggest that physicians in the People's Republic of China have participated in executions by organ removal., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The repeated waves of the COVID-19 pandemic have highlighted the necessity to optimize vaccine responses in immunocompromised populations. We investigated the safety and immunogenicity of a third, booster, dose of the Pfizer BNT162b2 vaccine in heart transplant (HT) patients., Methods: The cohort comprised 96 adult HT patients who received a third homologous dose of the BNT162b2 vaccine 168 days after the second dose. The vaccine-induced antibody responses of both receptor-binding domain (RBD) IgG and neutralizing antibodies were assessed in all patients, with a positive antibody response being defined as the presence of either IgG anti-RBD or neutralizing antibodies. For a subset of patients, T cell response was also studied., Results: The third dose was associated with a low rate of adverse events, mostly mild pain at the injection site. No serious adverse events were recorded, and there were no episodes of rejection. At 18 days following the third dose of the vaccine, the positive antibody response increased from 23% to 67%, with a corresponding increase in neutralizing capacity. The third dose elicited SARS-CoV-2 neutralization titers >9-fold and IgG anti-RBD antibodies >3-fold of the range achieved after the two primary doses. Mycophenolate use, lower eGFR and higher C-reactive protein were independently associated with a reduced likelihood of generating an immune response. Importantly, a specific T-cell response following the third dose was evident in the majority of transplant recipients., Conclusions: An homologous third booster dose of the BNT162b2 vaccine gave overall consistent tolerability and a good safety profile, while eliciting humoral and cellular immune responses., Competing Interests: Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Data on the safety and efficacy of SARS-CoV-2 vaccines in immunocompromised populations are sparse., Methods: We conducted a prospective study of 77 heart transplant (HT) recipients vaccinated with two doses of BNT162b2 vaccine and monitored for adverse events following both doses, the receptor-binding domain (RBD) IgG response, and neutralizing antibodies., Results: BNT162b2 vaccination was associated with a low rate of adverse events, characterized mostly by pain at the injection site. By a mean 41 days post second dose there were no clinical episodes of rejection, as suggested by a troponin leak or allograft dysfunction. At a mean 21 days following the second dose, IgG anti-RBD antibodies were detectable in 14 (18%) HT recipients. Immune sera neutralized SARS-CoV-2 pseudo-virus in 8 (57%) of those with IgG anti-RBD antibodies. Immunosuppressive regimen containing mycophenolic acid was associated with lower odds of an antibody response (OR = 0.12, p = 0.042)., Conclusions: Whether a longer time-frame for observation of an antibody response is required after vaccination in immunosuppressed individuals remains unknown., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality after heart transplantation (HT). Statins are known to have immunomodulatory and antiinflammatory effects, and perioperative statin therapy has been associated with reduced cardiovascular complications and improved outcomes after cardiac and noncardiac surgery. Thus, we investigated the influence on PGD of statin therapy administered to recipients before HT., Methods: A retrospective cohort study was conducted on 275 HT recipients assessed from 1997 to 2017; 167 (61%) had received statins during the month prior to and at time of transplantation, whereas 108 (39%) had not. Endpoints included PGD (defined according to the International Society of Heart and Lung Transplantation consensus statement), in-hospital mortality, and 1-year and 5-year survival., Results: PGD incidence was significantly lower for statin-treated patients (21 vs 60%, P < .001). Multivariable analysis demonstrated that pre-HT statin therapy was independently associated with a significant 65% reduced risk for PGD and a 73% reduced risk for in-hospital mortality. One- and five-year mortality, adjusted for age, sex, and amiodarone therapy, were significantly lower for recipients treated with statins (hazard ratio 0.33 and 0.39, 95% confidence interval 0.17-0.63 and 0.22-0.68, respectively; P = .001)., Conclusions: Pre-HT statin therapy was independently associated with a reduced risk for PGD and mortality. Our results also suggested that statins have a beneficial prognostic impact on heart failure patients awaiting HT., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Donor thyroid hormone (TH) supplementation therapy is widely used. Recent reports suggested an increased risk of graft dysfunction in heart transplant (HTx) recipients not receiving TH supplementation. Our aim was to determine the effect of a donor TH supplementation in a large contemporary HTx cohort., Methods: We analyzed data reported to the International Society for Heart and Lung Transplantation Registry on adult HTx recipients transplanted from 2006 to 2016. Early graft loss (EGL) was defined as death or retransplant because of graft failure within 48 hours of transplant. Logistic regression and propensity score analyses were performed., Results: There were 23,002 adult HTx recipients transplanted during the study period for whom data on the use of donor TH supplementation were provided to the Registry. There were 15,821 recipients whose donors had received TH supplementation, and 7,181 who had not. Multivariable analysis showed donor TH therapy to be associated with an increased risk for EGL (odds ratio, 1.51; 95% CI, 1.13-2.06; p < 0.001). Long-term survival was similar, irrespective of donor TH supplementation. Recipients whose donors had received TH supplementation exhibited a lower 8-year incidence of vasculopathy (hazard ratio, 0.90; 95% CI, 0.85-0.97; p = 0.003). These results remained consistent in a propensity-matched analysis., Conclusions: Donor TH therapy is independently associated with an increased risk of EGL. Whether this is a result of the donor allograft intrinsic characteristics related to the reasons why TH was used or whether this is a result of a TH withdrawal effect, which could be mitigated by administration of TH to the recipient, should be further studied., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated the implications of early recurrent 1R rejections for long-term outcomes after heart transplantation (HT) and evaluated the prognostic significance of 1990 ISHLT grading 1B/2 versus 1A., Methods: Data on all patients who underwent HT between 1992 and 2017 were reviewed. Patients with ≥2 endomyocardial biopsies graded 1R in the first 3 months were classified as "recurrent 1R." Those patients were further categorized according to 1A vs. 1B/2. Outcomes (>3 months) were long-term rejections and the combined endpoint of cardiac allograft vasculopathy (CAV) and cardiovascular (CV) mortality., Results: Sixty-nine out of 228 patients were classified as recurrent grade 1R. In the recurrent 1R group, 2R rejection rate was significantly higher (2.6 ± 0.6 vs 1.2 ± 0.4, p = 0.03), while survival free of rejections was lower (5-year: 57.1% vs. 72.3%, p = 0.022). Multivariate analysis showed that early recurrent 1R rejection was associated with a 30% increased risk for subsequent major rejection. Among 28 patients classified as 1B/2 of the recurrent group, rejection scores were higher, while survival free of rejections was lower, compared to 37 patients of the recurrent group classified as 1A (5-year: 57.1% vs. 72.7%, p = 0.013). Kaplan-Meier analysis showed that CAV/CV mortality at 10 years of follow-up was significantly higher among the recurrent 1R group (38% vs. 18% p < 0.05). Multivariate analysis showed that early recurrent 1R rejections were associated with a 2.5-fold increased risk for CAV/CV mortality., Conclusion: Early recurrent grade 1R rejections negatively affect long-term outcomes. The adverse outcomes are experienced mainly by 1R patients subcategorized as1B/2 and not 1A., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The HeartMate 3 left ventricular assist device (Abbott, Chicago, IL) is designed to provide circulatory support with enhanced hemocompatibility for patients with advanced heart failure. The purpose of this study was to compare the surgical outcomes between patients treated during the European Conformity Mark (CE Mark [CEM]) clinical trial and those treated in the postmarket era., Methods: The prospective, observational, multinational ELEVATE (Evaluating the HeartMate 3 with Full MagLev Technology in a Post-Market Approval Setting) registry includes patients receiving the HeartMate 3 following CEM approval. Outcomes of patients in the ELEVATE registry are compared with patients in the CEM trial., Results: Compared with the CEM trial (N = 50), the ELEVATE registry group (N = 463) was more severely ill, with more patients classified as INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 1 to 2 (32% versus 10%; p < 0.001). The CEM trial group was younger and underwent fewer concomitant valve procedures. After adjustment for differences in baseline characteristics, the 30-day survival was comparable between the ELEVATE registry and CEM trial groups (95% versus 98%; p = 0.46). Length of intensive care unit stay was similar between the ELEVATE registry (7 days) and CEM trial (6 days) groups. Most adverse event rates were comparable between the 2 groups. ELEVATE registry patients had a lower rate of cardiac arrhythmias (13% versus 28%; p = 0.009). With increasing experience, the implant technique has evolved to include more versatile approaches such as less invasive and off-pump implantation., Conclusions: The 30-day outcomes for ELEVATE registry patients are comparable despite being sicker than CEM trial patients. Adverse event rates remain low, with no cases of pump thrombosis within the first 30 days. Implant techniques have evolved to include more versatile approaches., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Significant right ventricular failure accompanying left ventricular failure was treated by implantation of the fully magnetically levitated centrifugal HeartMate 3 ventricular assist device as biventricular (BiVAD) support in 14 patients at 6 medical centers worldwide. The clinical details of this first multicenter experience are presented. Nine of these patients (64%) were alive as of January 1, 2018. Eight of the 9 have continued on BiVAD support for 95 to 636 (mean 266) days: 7 at home, and 1 successfully transplanted after 98 days of support., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx., Methods: The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses., Results: Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients., Conclusions: Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Previous publications have described unethical organ procurement procedures in the People's Republic of China. International awareness and condemnation contributed to the announcement abolishing the procurement of organs from executed prisoners starting from January 2015. Eighteen months after the announcement, and aligned with the upcoming International Congress of the Transplantation Society in Hong Kong, this paper revisits the topic and discusses whether the declared reform has indeed been implemented. China has neither addressed nor included in the reform a pledge to end the procurement of organs from prisoners of conscience, nor has the government initiated any legislative amendments. Recent reports have discussed an implausible discrepancy of officially reported steady annual transplant numbers and a steep expansion of the transplant infrastructure in China. This paper expresses the viewpoint that, in the current context, it is not possible to verify the veracity of the announced changes, and it thus remains premature to include China as an ethical partner in the international transplant community. Until we have independent and objective evidence of a complete cessation of unethical organ procurement from prisoners, the medical community has a professional responsibility to maintain the academic embargo on Chinese transplant professionals., (© 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.)

The allocation system of donor organs for transplantation may affect their scarcity. In 2008, Israel's Parliament passed the Organ Transplantation Law, which grants priority on waiting lists for transplants to candidates who are first-degree relatives of deceased organ donors or who previously registered as organ donors themselves. Several public campaigns have advertised the existence of the law since November 2010. We evaluated the effect of the law using all deceased donation requests made in Israel during the period 1998-2015. We use logistic regression to compare the authorization rates of the donors' next of kin in the periods before (1998-2010) and after (2011-2015) the public was made aware of the law. The authorization rate for donation in the period after awareness was substantially higher (55.1% vs. 45.0%, odds ratio [OR] 1.43, p = 0.0003) and reached an all-time high rate of 60.2% in 2015. This increase was mainly due to an increase in the authorization rate of next of kin of unregistered donors (51.1% vs. 42.2%). We also found that the likelihood of next-of-kin authorization for donation was approximately twice as high when the deceased relative was a registered donor rather than unregistered (89.4% vs. 44.6%, OR 14.27, p < 0.0001). We concluded that the priority law is associated with an increased authorization rate for organ donation., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Organ procurement from executed prisoners in China is internationally condemned, yet this practice continues unabated in 2014. This is despite repeated announcements from Chinese authorities that constructive measures have been undertaken to conform to accepted ethical standards. While there is unanimous agreement on the unethical nature of using organs from executed prisoners, due to its limitations on voluntary and informed consent, there is insufficient coverage of forced organ procurement from prisoners of conscience without consent. Strategies to influence positive change in China over the last few decades have failed to bring this practice to an end. While organ donation and transplantation services in China have undergone considerable structural changes in the last few years, fundamental attempts to shift practice to ethically sourced organs have floundered. In this article, we discuss the organ trade in China, reflect upon organ procurement from executed prisoners (including both capital prisoners and prisoners of conscience) and provide an overview of contradictory Chinese efforts to halt forced organ procurement from executed prisoners. Finally, we highlight current actions being taken to address this issue and offer comprehensive recommendations to bring this ethically indefensible practice to an immediate end., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Israel's organ donation rate has always been among the lowest in Western countries. In 2008 two new laws relevant to organ transplantation were introduced. The Brain-Respiratory Death Law defines the precise circumstances and mechanisms to determine brain death. The Organ Transplantation Law bans reimbursing transplant tourism involving organ trade, grants prioritization in organ allocation to candidates who are registered donors and removes disincentives for living donation by providing modest insurance reimbursement and social supportive services. The preliminary impact of the gradual introduction and implementation of these laws has been witnessed in 2011. Compared to previous years, in 2011 there was a significant increase in the number of deceased organ donors directly related to an increase in organ donation rate (from 7.8 to 11.4 donors per million population), in parallel to a significant increase in the number of new registered donors. In addition the number of kidney transplantations from living donors significantly increased in parallel to a significant decrease in the number of kidney transplantations performed abroad (from 155 in 2006 to 35 in 2011). The new laws have significantly increased both deceased and living organ donation while sharply decreasing transplant tourism., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Internationally accepted ethical standards are unequivocal in their prohibition of the use of organs recovered from executed prisoners: yet this practice continues in China despite indications that Ministry of Health officials intend to end this abhorrent practice. Recently published articles on this topic emphasize the medical complications that result from liver transplantation from executed 'donors' but scant attention is given to the source of the organs, raising concern that the transplant community may be becoming inured to unacceptable practice. Strategies to influence positive change in organ donation practice in China by the international transplant community are discussed. They include an absolutist policy whereby no clinical data from China is deemed acceptable until unacceptable donation practices end, and an incremental policy whereby clinical data is carefully evaluated for acceptability. The relative advantages and drawbacks of these strategies are discussed together with some practical suggestions for response available to individuals and the transplant community., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Antifreeze proteins (AFP) are associated with protection from freezing. We measured the effect of type I antifreeze protein on spontaneous bursting of mixed neuronal/glial cultures using a multi-electrode array culture system. Antifreeze protein (10mg/ml) reversibly depressed bursting activity without inhibiting mitochondrial oxidative capacity. The effect of antifreeze protein on cold/re-warming injury was investigated in rat hippocampal slice cultures. Compared to bovine serum albumin at a similar concentration, antifreeze protein protected hippocampal neurons from 8h of profound hypothermia at (4 degrees C) followed by re-warming. The protection observed is believed to be associated with the inhibitory effect of antifreeze protein., (Copyright 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Background: A bicuspid aortic valve (BAV) is a common congenital heart disease, which affects 1-2% of the population. However, the relationship between BAVs and aortic dilation has not been sufficiently elucidated., Methods: A total of 241 BAV patients who were referred to this hospital for cardiac surgery over a 4.75-year period were included in this study. In addition to the clinical characteristics of the included patients, the morphological features of the aortic valve and aorta, the length of the left main coronary artery, and the laboratory findings (the coagulation and hematological parameters as well as the total cholesterol concentration) were determined and compared with those of the tricuspid aortic valve (TAV) patients., Results: The BAV patients were younger than the TAV patients for a valve surgery in the last 3 months of the study period. The BAV patients were predominantly male. Most of the BAVs that were surgically treated were stenotic, regurgitant, or combined, and only 19 (7.88%) were normally functioning valves. According to echocardiography or operative records, 148 (78.31%) were type A, 31 (16.40%) were type B, and 10 (5.29%) were type C. The left main coronary artery was much shorter in the BAV patients than it was in the TAV patients. There was no significant difference between BAV and TAV patients in the total cholesterol concentrations; whereas differences were noted between patients receiving lipid-lowering therapy and those not receiving lipid-lowering therapy. The dimensions of the aortic root, sinotubular junction, and ascending aorta were beyond normal limits, while they were significantly smaller in the BAV patients than in the TAV patients. They were also much smaller in patients receiving statin therapy than those not receiving statin therapy in both groups. Moreover, the aortic dilation in the BAV group was found to be significantly associated with patient age., Conclusions: The BAV patients developed aortic wall and aortic valve disorders at a younger age than the TAV patients and were predominantly male. Aortic dilation was observed in the aortic root, sinotubular junction, and ascending aortic segments in both the BAV and TAV patients undergoing surgical aortic valve replacement, although the BAV patients had a smaller degree of dilation than the TAV patients, and dilation was also significantly age-related in this group. The shorter left main coronary artery that the BAV patients possess may contribute to the progressive course of aortic dilation that these patients experience. Statin therapy did not affect the aortic annulus in either group, but did decrease the dimensions of the aortic root, sinotubular junction and ascending aorta. In general, statin therapy had a better effect on the aortas of the TAV patients than it did on those of the BAV patients.

Background: Freeze-tolerant fish survive sub-zero temperatures by non-colligatively lowering the freezing temperature of their body fluids using anti-freeze proteins (AFPs). We sought to evaluate and compare the effects of prolonged sub-zero cryopreservation of transplanted rat hearts using AFP I or AFP III., Methods: Two heterotopic rat heart transplantation protocols were used. In Protocol 1 (n = 104), hearts (n = 8/group) were preserved for 12, 18 and 24 hours in University of Wisconsin solution (UW) at 4 degrees C, UW at -1.3 degrees C, UW/AFP I at -1.3 degrees C and UW/AFP III at -1.3 degrees C, with and without nucleation. Post-operative evaluation consisted of visual viability scoring of the hearts after 60 minutes. Protocol 2 (n = 58) involved evaluation of 24-hour post-transplant viability, echocardiography (fractional shortening [FS], left ventricular end-systolic and -diastolic diameter [ESD, EDD] and anterior and posterior wall systolic and diastolic thickness [AWT-S, AWT-D, PWT-S, PWT-D]), TUNEL staining and electron microscopy (EM) findings for hearts preserved for 18, 21 and 24 hours in UW at 4 degrees C or UW/AFP III at -1.3 degrees C., Results: Hearts preserved in UW at -1.3 degrees C with nucleation froze and died. Three of 8 hearts preserved in UW at 4 degrees C for 24 hours died, whereas all hearts preserved at -1.3 degrees C survived. Hearts preserved in UW/AFP for 18 and 24 hours at -1.3 degrees C had superior viability scores compared with those in UW at 4 degrees C. Hearts in AFP III at -1.3 degrees C displayed greater AWT-S and AWT-D (3.5 +/- 0.2 vs 2.4 +/- 0.2, p < 0.05, and 3.5 +/- 0.2 vs 2.2 +/- 0.2, p < 0.05, respectively) after 18-hour preservation. In the 21-hour preservation group, AFP-treated hearts displayed improved echocardiographic systolic contraction indices, including: improved FS (27 +/- 3.7 vs 15 +/- 4, p = 0.04); diminished ESD (0.28 +/- 0.57 vs 0.47 +/- 0.6, p < 0.05); greater AWT-S (3.4 +/- 0.18 vs 2.8 +/- 0.2, p < 0.05); and fewer positively TUNEL-stained nuclei per specimen (35 +/- 14 vs 5.3 +/- 2.7, p = 0.04). Also, improved EM scores were noted compared with UW at 4 degrees C., Conclusions: In prolonged sub-zero cryopreservation, AFPs protect the heart from freezing, improve survival and hemodynamics, and reduce apoptotic cell death.

The purpose of the present study was to evaluate whether AFPs protect the heart from freezing and improve survival and viability in subzero cryopreservation. Hearts were subject to 5 preservation protocols; University of Wisconsin solution (UW) at 4 degrees C, UW at -1.3 degrees C without nucleation, UW at -1.3 degrees C with nucleation, UW AFP I (15 mg/cm(3)) at -1.3 degrees C with nucleation, and in UW AFP III (15 mg/cm(3)) at -1.3 degrees C with nucleation. Hearts were preserved for 24, 28, and 32 h, rewarmed and connected to the working isolated perfusion system. Data [heart rate (HR), coronary flow (CF), and developed pressure (dP)] was collected 30 and 60 min after reperfusion. Hearts preserved at -1.3 degrees C without AFPs froze, while hearts preserved with AFP did not freeze when nucleation was initiated and survived. Survival and dP of hearts preserved for 24h at -1.3 degrees C using AFP III was better than those preserved at 4 degrees C, (dP; 1.4 vs. 0.8, p<0.05). Four of six hearts and six of six hearts died when preserved at 4 degrees C for 28 and 32 h, respectively, all of the hearts that were preserved at -1.3 degrees C with or without AFPs survived after 28 h (n=18) and 32 h (n=18). CF was higher in UW -1.3 degrees C group without attempted nucleation than in AFP I and AFP III groups after 28 and 32 h (3.4 vs. 1.7, p<0.05, and 3.4 vs. 1.7, p<0.05, respectively). In conclusion, AFPs were found to protect the heart from freezing and improve survival and dP (AFP III) in prolonged subzero preservation.

Background: Arctic fish survive subzero temperatures by producing a family of antifreeze proteins (AFPs) that noncolligatively lower the freezing temperature of their body fluids. We report 24-hour storage of mammalian hearts for transplantation at subzero temperatures using AFPs derived from arctic fish., Methods: Forty-two heterotopic transplantations were performed in isoimmune Sprague-Dawley rats. Harvested hearts were retrogradely infused with cold 4 degrees C University of Wisconsin (UW) solution and were preserved in a specialized cooling bath at two target temperatures, 4 degrees C and -1.3 degrees C for 12,18, and 24 hours (6 experiments/group). Preservation solutions were UW alone for the 4 degrees C group, and UW with 15 mg/mL AFP III for the -1.3 degrees C group. After hypothermic storage the hearts were heterotopically transplanted into isoimmune rats. Viability was assessed and graded on a scale of 0 to 6 (0 = no contractions to 6 = excellent contractions). Transplanted hearts were then fixed in vivo and were subject to electron microscopy and histopathologic examination., Results: None of the hearts preserved at -1.3 degrees C in UW/AFP III solution froze. All control hearts preserved at -1.3 degrees C without AFP protection froze and died at reperfusion. Viability of hearts preserved at -1.3 degrees C in UW/AFP III solution was significantly better after 18 hours of preservation, 30 and 60 minutes after reperfusion (median, 5 versus 3 and 6 versus 3, respectively; p < 0.05) and after 24 hours of preservation 30 and 60 minutes after reperfusion (median, 4.5 versus 1.5 and 5 versus 2, respectively; p < 0.05). Histologic and electron microscopy studies demonstrated better myocyte structure and mitochondrial integrity preservation with UW/AFP III solution., Conclusions: Antifreeze proteins prevent freezing in subzero cryopreservation of mammalian hearts for transplantation. Subzero preservation prolongs ischemic times and improves posttransplant viability.

Severe hypotensive reactions that occur during transfusions of blood products to non-transplanted patients were recently linked to the use of bedside leukocyte-reduction filters, sometimes in association with angiotensin-converting enzyme (ACE) inhibitor treatment. We present the first report of such reactions in patients who underwent orthotopic heart transplantation. Fourteen (47%) of the 30 transfused patients experienced severe hypotensive reaction during filtered transfusion of at least 1 unit of blood product, with a total of 24 episodes. Eleven (79%) of these patients were treated pre-operatively with ACE inhibitors.

Platelet transfusion and aprotinin administration improve platelet function and clinical hemostasis after extracorporeal circulation. To compare two methods of improving postoperative hemostasis, we preoperatively randomized 40 patients undergoing various open heart procedures into two groups. Group A included 20 patients who, immediately after bypass, received single-donor plateletpheresis concentrates collected from ABO-compatible donors (Baxter Autopheresis-C System). They were compared with 20 patients who received high-dose aprotinin (6 x 10(6) KIU) before and during cardiopulmonary bypass (group B). Group A patients showed significantly higher platelet count after single-donor plateletpheresis concentrate transfusion (157 +/- 36 x 10(9)/L compared with 118 +/- 42 x 10(9)/L (p < 0.05). However, platelet aggregation on extracellular matrix was better in group B (3.4 +/- 0.7 versus 2.8 +/- 0.9; p < 0.05). Total 24-hour blood loss and exposure to homologous blood products were significantly less in group B (396 +/- 125 mL and 1.1 +/- 1.6 units compared with 617 +/- 233 mL and 5.4 +/- 3.4 units; p < 0.01). Despite higher platelet count in patients after single-donor plateletpheresis concentrates transfusion, hemostasis in patients receiving aprotinin is better due to improved platelet function.

To evaluate the effect of low-dose aprotinin during cardiopulmonary bypass on platelet function and clinical hemostasis, 30 patients undergoing various cardiopulmonary bypass procedures employing bubble oxygenators were randomized to receive either low-dose aprotinin (2 x 10(6) KIU in the cardiopulmonary bypass priming solution, 15 patients [group A]) or placebo (15 patients [group B]). Blood samples were collected before and after cardiopulmonary bypass to assess platelet count and aggregation on extracellular matrix, which was studied by a scanning electron microscope. On a scale of 1 to 4 preoperative mean platelet aggregation grades were similar in both groups (3.8 +/- 0.5 and 3.5 +/- 0.5 for groups A and B, respectively). Postoperatively, platelet aggregation on extracellular matrix decreased slightly in group A (2.8 +/- 1.3; p < 0.01) and significantly in group B (1.3 +/- 0.5; p < 0.001). Eleven of the 15 patients in group A remained in aggregation grade 3 or 4 compared with none of the group B patients. Platelet count was similar in both groups preoperatively and postoperatively. Total 24-hour postoperative bleeding and blood requirement were lower in the aprotinin group (487 +/- 121 mL and 2.3 +/- 1.0 units) than in the placebo group (752 +/- 404 mL and 6.8 +/- 5.1 units; p < 0.01). These results show that the use of low-dose aprotinin during cardiopulmonary bypass provides improved postoperative hemostasis, which might be related to the protection of the platelet aggregating capacity.

To evaluate the functional integrity of platelets in patients administered the proteinase inhibitor aprotinin during cardiopulmonary bypass, 20 patients undergoing a complicated and prolonged open heart operation were studied. They were randomized to receive either a high dose of aprotinin (total dose, 6 to 7 x 10(6) KIU) before and during cardiopulmonary bypass (10 patients) or a placebo (10 patients). Blood samples were collected preoperatively, at the termination of bypass, and 90 minutes thereafter to assess platelet count and aggregation on extracellular matrix, which was studied by scanning electron microscopy. On a scale of 1 to 4, mean preoperative platelet aggregation grades were similar in both groups (3.5 +/- 0.5). Postoperatively, at the termination of cardiopulmonary bypass and 90 minutes thereafter, all 10 patients treated with aprotinin revealed normal, unchanged platelet aggregation (grade, 3.5 +/- 0.5), whereas all placebo-treated patients showed severely disturbed aggregation (grade, 1.4 +/- 0.5) (p less than 0.001). The platelet count was similar in both groups before and after operation (preoperatively, 182 +/- 75 x 10(9)/L and 146 +/- 30 x 10(9)/L, and postoperatively, 87 +/- 13 x 10(9)/L and 80 +/- 27 x 10(9)/L for the aprotinin and placebo groups, respectively). Total 24-hour postoperative bleeding and blood requirement were significantly lower in the aprotinin group (371 +/- 84 mL and 2 +/- 0.7 units, respectively) compared with the placebo group (608 +/- 28 mL and 3.4 +/- 1.3 units, respectively) (p less than 0.01). These results demonstrate that improved postoperative hemostasis is directly related to the complete preservation of platelet function achieved by the protective properties of aprotinin.

Review of 463 heart transplants was undertaken to examine the relationship between level of panel-reactive antibody (PRA) and a standard donor-specific lymphocytotoxic crossmatch (LXM) on the incidence of death from hyperacute, acute, and chronic rejection. Death from chronic rejection was defined as being caused by graft atherosclerosis. Hyperacute rejection was diagnosed in 18 allografts, and only two recipients had PRA greater than 10% and another two a positive LXM. Five-year actuarial freedom from death caused by all forms of rejection correlated with PRA values as follows: PRA 0% to 10% (415 patients), 85%; PRA 11% to 25% (29 patients), 68%; PRA greater than 25% (19 patients), 57% (p less than 0.005). Additionally, there was a positive linear relationship between PRA and duration of acute rejection episodes in the first 3 months after transplantation. A positive retrospective donor-specific LXM was present in 42 of 401 patients; most of them (32 patients) were low positive (10% to 50% cell death), and none could be correlated with antibody specificity toward donor HLA antigens. Five-year actuarial freedom from death caused by rejection was 83% in those with a negative LXM, 74% in those with low-positive, and 79% in those with high-positive LXM (p = NS). Negative LXM result did not reduce the risk of death caused by rejection in any of the PRA subgroups. While PRA greater than 10% is a risk factor for rejection-related events, a negative LXM in patients with an elevated PRA does not reduce the risk of death resulting from acute or chronic rejection.

The routine use of an arbitrary fixed left atrial (LA) pressure during volume load after aortocoronary bypass operation was compared with use of an individualized postoperative target LA pressure according to a calculated preoperative LA pressure in two groups of consecutive patients. The preoperative LA pressure of each patient was calculated from the preoperative left ventricular end-diastolic pressure (LVEDP) by the formula: mean LA pressure = 1.16 x LVEDP - 8.53. Left atrial pressure, mean arterial pressure, mean right atrial pressure, and cardiac output were measured simultaneously on arrival at the intensive care unit and 60 minutes later. Cardiac index (CI) and systemic vascular resistance (SVR) were calculated from the variables already mentioned. Results indicated a significantly higher CI and significantly lower SVR in patients in whom volume load was aimed at the calculated preoperative LA pressure. It was concluded that the optimal postoperative LA pressure is specific for each patient and depends on the preoperative LVEDP.