Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months.

We report orthotopic (life-supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti-CD40 monoclonal antibody-based immunosuppression. In this current study, life-supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti-inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective "multi-gene" xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective "multi-gene" modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans.

Anesthetic Considerations in Endovascular Repair of the Ascending Aorta.

Since the first endovascular aortic repair in 1990, endovascular devices and the indications for their use have significantly grown. Considerable progress has been made in endovascular devices and techniques, such that endovascular repair is now considered first-line treatment for patients with descending aortic disease. However, for patients with ascending aortic disease, open surgical repair with cardiopulmonary bypass and hypothermic cardiac arrest was the only option until recently. Although the outcomes for open surgical repair of the ascending aorta have improved over the years, approximately 30% of patients with an emergent surgical indication, such as type A aortic dissection, are considered to be too high risk for open repair. For these patients, endovascular repair of the ascending aorta offers a life-saving procedure. The ascending aorta is regarded as the final frontier for endovascular therapy. Endovascular repair of it has posed a formidable challenge thus far, due to its unique anatomy, hemodynamic forces, and lack of an appropriate stent-graft designed specifically for the ascending aorta. Although currently there are no comprehensive data from randomized clinical trials, there are several case series and case reports that have shown favorable outcomes. Improvements in available devices soon will drive an exponential increase in the number of patients undergoing endovascular ascending aortic repair. In this review, the authors discuss multiple aspects of endovascular ascending aortic repair including the unique surgical and anesthetic considerations, the devices used, and the available outcomes data, and future directions are also explored.

Acute Intracardiac Thrombosis and Pulmonary Thromboembolism After Cardiopulmonary Bypass: A Systematic Review of Reported Cas.

Intracardiac thrombosis (ICT) and pulmonary thromboembolism (PE) after cardiopulmonary bypass (CPB) are life-threatening events, but pathological mechanisms are not yet well defined. The aim of this review is to provide an update of case literature of a postbypass hypercoagulable state. Case commonalities among 48 ICT/PE events included congestive heart failure (50%), platelet transfusion (37.5%), CPB duration greater than 3 hours (37.5%), and aortic injury (27.1%). Preexisting thrombophilia was rarely reported, and 16.7% had low activated clotting time, ≤400 seconds during CPB. Mortality rate was very high (85.4%), despite attempted thrombectomy and supportive therapy. Thrombolytic therapy was infrequently used (5 of 48 times), but its efficacy is questionable due to common use of antifibrinolytic therapy (77.1% of cases). Acute ICT/PE events appear to rarely occur, but common features include prolonged CPB, depressed myocardial function, major vascular injury, and hemostatic interventions. Further efforts to elucidate pathomechanisms and optimize anticoagulation during CPB and hemostatic interventions after CPB are warranted.

Intra-abdominal Hypertension and Postoperative Kidney Dysfunction in Cardiac Surgery Patients.

OBJECTIVE: To determine the incidence of intra-abdominal hypertension (IAH) in adult cardiac surgery patients and its association with postoperative kidney dysfunction. DESIGN: Prospective cohort study. SETTING: Single tertiary-care university hospital. PARTICIPANTS: Forty-two adult patients having cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Intra-abdominal pressure (IAP) was measured preoperatively, immediately after surgery, and at the following time points after surgery: 3 hours, 6 hours, 12 hours, and 24 hours. Urine neutrophil gelatinase-associated lipocalin (NGAL) levels were measured as a marker of kidney dysfunction at the following time points: prior to surgery, immediately after surgery, 4 to 6 hours after surgery, and 16-to-18 hours after surgery. MEASUREMENTS AND MAIN RESULTS: Two hundred fifty-two IAPs were measured, and 90 (35.7%) showed IAH. Thirty-five of 42 patients (83.3%) had IAH at 1 time point or more. Peak urine NGAL levels were lower in patients with normal IAP (mean difference = -130.6 ng/mL [95% CI = -211.2 to -50.1], p = 0.002). There was no difference in postoperative kidney dysfunction by risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) criteria in patients with normal IAP (mean difference = -31.4% [95% CI = -48.0 to 6.3], p = 0.09). IAH was 100% sensitive for predicting postoperative kidney dysfunction by RIFLE criteria, but had poor specificity (54.8%). CONCLUSIONS: IAH occurs frequently during the perioperative period in cardiac surgery patients and may be associated with postoperative kidney dysfunction.

Effect of cardiopulmonary bypass on platelet mitochondrial respiration and correlation with aggregation and bleeding: a pilot study.

BACKGROUND: Cardiopulmonary bypass (CPB) may cause platelet dysfunction, contributing to bleeding. There are no investigations of how CPB affects platelet mitochondrial respiration and what correlation this has with platelet aggregation and bleeding. METHODS: We studied platelet mitochondrial respiration and aggregation in eighteen adult cardiac surgery patients having CPB. The relationships between respiration, aggregation and postoperative bleeding were analyzed. RESULTS: Platelet respiration, reflected by the respiratory control ratio (RCR), was unchanged after CPB (mean difference in RCR= -0.02 (95% CI=-1.45 to 1.42), p=0.98). Further, there were no significant relationships between indexed adenosine diphosphate (ADP) or thrombin receptor-activating peptide (TRAP)-induced aggregation and the RCR (p=0.12 and p=0.41). Only post-CPB ADP - induced aggregation correlated with 24-hr chest tube output (p=0.04), but indexing for platelet count attenuated the effect (p=0.07). CONCLUSION: Platelet mitochondrial respiration is preserved after CPB and is not correlated with aggregation or bleeding. Only post-CPB, ADP-induced aggregation correlates with postoperative bleeding.

Anesthetic management of robotically assisted totally endoscopic coronary artery bypass surgery (TECAB).

Over the last decade, TECAB has matured into a reproducible technique associated with low incidence of both mortality and morbidity, as well as superior quality of life, when compared with open CABG surgery. However, TECAB also is associated with important and specific challenges for the anesthesiology team, particularly with regard to the physiologic stresses of OLV, placement of special catheters, and induced capnothorax. As the technology supporting robotic surgery evolves and familiarity with, and confidence in, TECAB increases, the authors anticipate increasingly widespread use of these procedures in an increasingly fragile and problematic patient population who will require the support of a skilled and vigilant anesthesiology team.

Intraoperative Management of an Orthotopic Porcine-to-Human Cardiac Xenotransplant.

We report the intraoperative management of an orthotopic cardiac xenotransplant in a 57-year-old man with nonischemic cardiomyopathy requiring venoarterial extracorporeal membrane oxygenation. Transesophageal echocardiography was used for preharvest assessment. Continuous ex vivo perfusion of the heart was performed. Steps were taken to avoid potential xenozoonosis transmission to other patients and staff. Preclinical experience guided our intraoperative management in controlling hemodynamics and using prophylactic antiarrhythmic medications. Echocardiography aided in the diagnosis of aortic dissection in the patient after transplant. Intraoperative cardiac function was excellent. The patient was weaned from all mechanical support 4 days after transplant.

Reevaluating the Ethical Issues in Porcine-to-Human Heart Xenotransplantation.

A major limiting factor with heart allotransplantation remains the availability of organs from deceased donors. Porcine heart xenotransplantation could serve as an alternative source of organs for patients with terminal heart failure. A first-in-human porcine xenotransplantation that occurred in January 2022 at the University of Maryland Medical Center provided an opportunity to examine several ethical issues to guide selection criteria for future xenotransplantation clinical trials. In this article, the authors, who are clinicians at UMMC, discuss the appropriate balancing of risks and benefits and the significance, if any, of clinical equipoise. The authors also review the alleged role of the psychosocial evaluation in identifying patients at an elevated risk of posttransplant noncompliance, and they consider how the evaluation's implementation might enhance inequities among diverse populations. The authors argue that, based on the principle of reciprocity, psychosocial criteria should be used, not to exclude patients, but instead to identify patients who need additional support. Finally, the authors discuss the requirements for and the proper assessment of informed and voluntary consent from patients being considered for xenotransplantation.

Ethical considerations during a pioneering surgical procedure: porcine cardiac xenotransplantation.

Preclinical advances in life-sustaining porcine cardiac xenotransplantation from donor pigs to baboons have paved the way for the performance of porcine cardiac xenotransplantation in a human. This procedure was performed with emergency use authorisation granted by the United States Food and Drug Administration under the umbrella of investigational new drug use on compassionate grounds. The patient was denied candidacy for durable mechanical circulatory support and heart transplantation as a result of non-adherence to medical advice. Successful porcine cardiac xenotransplantation in humans will significantly increase the availability of potential donor organs for long-term management of end-stage heart failure. Human porcine cardiac xenotransplantation is associated with ethical conflicts encompassing multiple ethical principles which are not mutually exclusive and are sometimes conflicting. This article focuses on some of the ethical conflicts encountered in relation to the use of mechanical circulatory support, pretransplant evaluation, shared decision making during informed consent, infectious disease risk, preclinical and clinical testing, and the role of regulatory bodies during performance of the first human porcine cardiac xenotransplantation. An increase in human trials of xenotransplantation procedures is imminent. Potential ethical conflicts associated with xenotransplantation should be addressed appropriately.

Anatomical Differences Between Human and Pig Hearts and Their Relevance for Cardiac Xenotransplantation Surgical Technique.

Cardiac xenotransplantation has been proposed to bridge the gap between supply and demand for patients with end-stage heart failure requiring transplantation. However, differences in pig anatomy compared with human anatomy require modification of the surgical approach. In addition, careful consideration should be given to size matching before transplantation. (Level of Difficulty: Advanced.).

Blood Cardioplegia Induction, Perfusion Storage and Graft Dysfunction in Cardiac Xenotransplantation.

Background: Perioperative cardiac xenograft dysfunction (PCXD) describes a rapidly developing loss of cardiac function after xenotransplantation. PCXD occurs despite genetic modifications to increase compatibility of the heart. We report on the incidence of PCXD using static preservation in ice slush following crystalloid or blood-based cardioplegia versus continuous cold perfusion with XVIVO© heart solution (XHS) based cardioplegia. Methods: Baboons were weight matched to genetically engineered swine heart donors. Cardioplegia volume was 30 cc/kg by donor weight, with del Nido cardioplegia and the addition of 25% by volume of donor whole blood. Continuous perfusion was performed using an XVIVO © Perfusion system with XHS to which baboon RBCs were added. Results: PCXD was observed in 5/8 that were preserved with crystalloid cardioplegia followed by traditional cold, static storage on ice. By comparison, when blood cardioplegia was used followed by cold, static storage, PCXD occurred in 1/3 hearts and only in 1/5 hearts that were induced with XHS blood cardioplegia followed by continuous perfusion. Survival averaged 17 hours in those with traditional preservation and storage, followed by 11.47 days and 15.03 days using blood cardioplegia and XHS+continuous preservation, respectively. Traditional preservation resulted in more inotropic support and higher average peak serum lactate 14.3±1.7 mmol/L compared to blood cardioplegia 3.6±3.0 mmol/L and continuous perfusion 3.5±1.5 mmol/L. Conclusion: Blood cardioplegia induction, alone or followed by XHS perfusion storage, reduced the incidence of PCXD and improved graft function and survival, relative to traditional crystalloid cardioplegia-slush storage alone.

Is an intraaortic balloon pump a contraindication to robotic totally endoscopic coronary artery bypass?

BACKGROUND: The success of robotic totally endoscopic coronary artery bypass (TECAB) in recent years has led to the expansion of the procedure to patients with more severe disease. Outcomes with these patients have not yet been well characterized, and no reports on TECAB performed in patients with a preoperatively placed intraaortic balloon pump (IABP) are available. We present our initial experience with this patient population. PATIENTS AND METHODS: We evaluated 5 patients with unstable angina or impaired left ventricular function requiring a preoperatively placed IABP who underwent TECAB using the daVinci telemanipulation system. Procedures were performed either on the beating heart using an endostabilizer (n = 2) or on the arrested heart using remote access perfusion and aortic balloon endoocclusion (n = 3). The median patient age was 67 years (range, 41-73 years), with a median preoperative ejection fraction of 43% (range, 26%-58%) and median EuroSCORE of 5 (range, 3-8). RESULTS: There were no major intraoperative technical issues. The median length of stay in the hospital and intensive care unit was 8 days (range, 5-13 days) and 66 hours (range, 41-142 hours), respectively. There were no intraoperative or 30-day mortalities. CONCLUSIONS: This early experience suggests that TECAB is feasible in patients with a preoperatively placed IABP. Both the beating heart and arrested heart versions can be used in this patient population, further broadening the spectrum of applicability of this procedure.

A Failed Cardiac Surgery Program in an Underserved Minority Population County Reimagined: The Power of Partnership.

Background Prince George's County Maryland, historically a medically underserved region, has a population of 909 327 and a high incidence of cardiometabolic syndrome and hypertension. Application of level I evidence practices in such areas requires the availability of highly advanced cardiovascular interventions. Donabedian principles of quality of care were applied to a failing cardiac surgery program. We hypothesized that a multidisciplinary application of this model supported by partnership with a university hospital system could result in improved quality care outcomes. Methods and Results A 6-month assessment and planning process commenced in July 2014. Preoperative, intraoperative, and postoperative protocols were developed before program restart. Staff education and training was conducted via team simulation and rehearsal sessions. A total of 425 patients underwent cardiac surgical procedures. Quality tracking of key performance measures was conducted, and 323 isolated coronary artery bypass grafting procedures were performed from July 2014 to December 2019. Key risk factors in our patient demographic were higher than the Society of Thoracic Surgeons national mean. Risk-adjusted outcome data yielded a mortality rate of 0.3% versus 2.2% nationally. The overall major complication rate was lower than expected at 7.1% compared with 11.5% nationally. Readmission rate was less than the Society of Thoracic Surgeons mean for isolated coronary artery bypass grafting (4.0% versus 10.1%, P<0.0001). Significant differences in 6 key performance outcomes were noted, leading to a 3-star Society of Thoracic Surgeons designation in 7 of 8 tracking periods. Conclusions Excellent outcomes in cardiac surgery are attainable following program renovation in an underserved region in the setting of low volume. The principles and processes applied have potential broad application for any quality improvement effort.

Early Experience With Preclinical Perioperative Cardiac Xenograft Dysfunction in a Single Program.

BACKGROUND: Perioperative cardiac xenograft dysfunction (PCXD) was described by McGregor and colleagues as a major barrier to the translation of heterotopic cardiac xenotransplantation into the orthotopic position. It is characterized by graft dysfunction in the absence of rejection within 24 to 48 hours of transplantation. We describe our experience with PCXD at a single program. METHODS: Orthotopic transplantation of genetically engineered pig hearts was performed in 6 healthy baboons. The immunosuppression regimen included induction by anti-CD20 monoclonal antibodies (mAb), thymoglobulin, cobra venom factor, and anti-CD40 mAb, and maintenance with anti-CD40 mAb, mycophenolate mofetil, and tapering doses of steroids. Telemetry was used to assess graft function. Extracorporeal membrane oxygenation was used to support 1 recipient. A full human clinical transplantation team was involved in these experiments and the procedure was performed by skilled transplantation surgeons. RESULTS: A maximal survival of 40 hours was achieved in these experiments. The surgical procedures were uneventful, and all hearts were weaned from cardiopulmonary bypass without issue. Support with inotropes and vasopressors was generally required after separation from cardiopulmonary bypass. The cardiac xenografts performed well immediately, but within the first several hours they required increasing support and ultimately resulted in arrest despite maximal interventions. All hearts were explanted immediately; histology showed no signs of rejection. CONCLUSIONS: Despite excellent surgical technique, uneventful weaning from cardiopulmonary bypass, and adequate initial function, orthotopic cardiac xenografts slowly fail within 24 to 48 hours without evidence of rejection. Modification of preservation techniques and minimizing donor organ ischemic time may be able to ameliorate PCXD.

Aortic valve bypass surgery: midterm clinical outcomes in a high-risk aortic stenosis population.

BACKGROUND: Aortic valve bypass (AVB; apicoaortic conduit) surgery relieves aortic stenosis (AS) by shunting blood from the apex of the left ventricle to the descending thoracic aorta through a valved conduit. We have performed AVB surgery as an alternative to conventional aortic valve replacement for high-risk AS patients. METHODS AND RESULTS: Between 2003 and 2007, 31 high-risk AS patients were treated with AVB surgery. Twenty-two patients (71%) were undergoing reoperation with patent coronary bypass grafts, and 5 (16%) had a porcelain ascending aorta. The average age was 81 years. Cardiopulmonary bypass was used for 19 of 31 patients (61%); the median duration of cardiopulmonary bypass was 19 minutes. Cross-clamp time for all patients was 0 minutes. Perioperative mortality was 13% (4 of 31 patients); no perioperative deaths occurred in the last 16 consecutive patients. One patient experienced a stroke related to intraoperative hypotension. No strokes have occurred during follow-up. Renal function was unchanged after AVB (preoperative creatinine, 1.3+/-0.5 mg/dL; postoperative creatinine, 1.2+/-0.5 mg/dL). The mean gradient across the native aortic valve decreased from 43.5+/-15 to 10.4+/-5.4 mm Hg. Echocardiographically determined conduit flow expressed as a percentage of total cardiac output was 72+/-12%. CONCLUSIONS: AVB surgery is an important therapeutic option for high-risk patients with symptomatic AS. Ventricular outflow is distributed in a predictable fashion between the conduit and the left ventricular outflow tract, and AVB surgery reliably relieves AS. Stroke and renal dysfunction were uncommon.

On-pump beating-heart with axillary artery perfusion: a solution for robotic totally endoscopic coronary artery bypass grafting?

Robotic totally endoscopic coronary artery bypass grafting (TECAB) can be performed on the arrested heart or on the beating heart without heart-lung machine support. In high-risk patients or in patients where technical difficulties are expected with a complete off-pump approach, a beating heart concept with heart-lung machine support can be an important option. Femoral arterial cannulation is associated with additional risk of retrograde cerebral embolization, and axillary cannulation is an accepted method in aortic surgery. We describe a case where an axillary artery cannulation method was used for the first time in TECAB performed with the da Vinci telemanipulation system.