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.

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.).

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.

Intraoperative echocardiographic assessment of mitral valve translocation.

OBJECTIVES: The aim of this study was to present a rigorous method to analyse the intraoperative echocardiographic images from the novel mitral translocation procedure, which assesses the changes in mitral structure and function and compares this data to a control group of patients who have no mitral regurgitation (MR). METHODS: Transoesophageal echocardiography was post-processed using dedicated 3D software. Ten patients with normal mitral valves (MV) undergoing non-mitral cardiac surgery served as controls. Mitral coaptation area, mid-leaflet coaptation length and mitral annular circumference were measured in 3D. RESULTS: Twenty-three consecutive patients with severe secondary MR underwent MV translocation. All patients had none/trace MR post-translocation. The mean coaptation surface area increased from 63 to 427 mm2 (P < 0.001) and coaptation length increased from 1.0 to 10.5 mm (P < 0.001). The control group coaptation surface area (136 mm2) and length (2.5 mm) were greater than pre-translocation (P = 0.019; P < 0.001) and less than post-translocation (P < 0.001; P < 0.001). 3D mitral annular circumference in the translocation group decreased 15% (130-110 mm) (P < 0.001). Post-translocation, the mean gradient was 2(2-3) mmHg with the diastolic mitral orifice area of 3.4 ± 0.3 cm2 by planimetry and 3.5 ± 0.3 cm2 by pressure half-time. The coaptation to septum distance remained unchanged (P = 0.305) without systolic anterior leaflet motion. CONCLUSIONS: This echocardiographic analysis method demonstrates that MV translocation abolishes secondary MR, increases coaptation area and length and produces acceptable diastolic function. This method of analysis should allow precise structural and quantitative assessment of the durability of the repair in future long-term follow-up.

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.

Translocation of the Mitral Valve in an Acute Large Animal Model.

Current repair options for functional mitral regurgitation (FMR) are not durable and do not adequately address underlying pathophysiology including leaflet tethering and insufficient coaptation. The feasibility of mitral valve translocation as a repair strategy for FMR was examined in normal swine. Seven pigs (median 62 kg, IQR 55-65 kg) with normal cardiac function were implanted with a 1-cm frustum-shaped pericardial patch inserted between the native mitral annulus and intact mitral leaflets. Operative survival was 100% with no post-procedure mitral stenosis, systolic anterior motion, or central mitral regurgitation observed on echocardiography. Post-translocation mean gradient was 3.5 mmHg (IQR 1.5-4 mmHg); trace or mild suture line leaks on the atrial suture line were noted in 5/7 pigs. Median leaflet coaptation increased from 2.4 (IQR 2.1-4.3 mm) to 12.4 mm (IQR 10.8-13.4 mm) after translocation (P = 0.016). Translocation dramatically increases leaflet coaptation without impairing diastolic function in animals with normal left ventricular function and is a promising technique for repair of FMR. Implantation of a 1.0-cm circumferential pericardial patch (mitral valve translocation) increases leaflet coaptation in a normal animal model.

A Pharmacokinetic and Plasmin-Generation Pharmacodynamic Assessment of a Tranexamic Acid Regimen Designed for Cardiac Surgery With Cardiopulmonary Bypass.

OBJECTIVES: To examine the pharmacokinetics (PK) and pharmacodynamics of a tranexamic (TXA) regimen designed for cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A pilot study quantifying TXA concentrations, fibrinolysis markers, and a plasmin- generation (PG) assay. For comparison, PG assay was performed on pooled normal plasma (PNP) with varying TXA concentrations. SETTING: A single-center, tertiary, academic medical center. PARTICIPANTS: Twenty patients undergoing cardiac surgery with CPB for valve surgery and/or coronary artery bypass grafting. INTERVENTION: TXA 100 mg/h infusion for 5 hours starting before incision; 1 g TXA in CPB prime and 1 g TXA at CPB end prior to heparin reversal. MEASUREMENTS AND MAIN RESULTS: The PK fit a 2-compartment disposition model. TXA concentrations were above 15 mg/L in all patients during CPB through 2 hours post-TXA infusion. During and after CPB, the TXA regimen decreased the median peak PG by 60% (95% confidence interval [CI], 56%-62%). Lowest median peak PG occurred 15 minutes postprotamine. Peak median D-dimer level of 1.24 (0.95-1.71; 95% CI) mg/L occurred at 15 minutes postprotamine and baseline-adjusted ΔD dimer correlated with increased CPB time (p = 0.004) and lower TXA level (p = 0.001). The median 24-hour chest tube output was 447 (330-664; 95% CI) mL. PG assay on PNP revealed a plateau inhibition at 5 mM TXA (786 mg/L). CONCLUSIONS: This regimen, with total perioperative dose of 2.5 grams, provided TXA concentrations above 15 mg/L for all patients from CPB initiation through 2 hours post-TXA. PG was significantly inhibited (p < 0.0001) during and after CPB, with maximum inhibition measured at 15 minutes after protamine administration.

In vitro effects of emicizumab on activated clotting time in blood samples from cardiac surgical patients.

BACKGROUND: Heparin management in hemophilia A (HA) patients with a factor VIII (FVIII) inhibitor can be challenging due to severe activated clotting time (ACT) prolongations. It is important to better understand the impact of emicizumab, a FVIII mimetic on ACT, and tissue factor (TF)-based coagulation assays. METHODS: Whole blood from 18 patients undergoing cardiopulmonary bypass (CPB) were mixed in vitro with pooled normal plasma, FVIII-deficient or FVIII-inhibitor plasma to affect functional FVIII levels. ACTs and heparin concentration by protamine titration were measured in whole blood mixture with/without emicizumab (50-100 µg/ml). Thrombin generation and plasmin generation were measured in the patient's plasma mixed with normal plasma or FVIII-inhibitor plasma to assess the impact of emicizumab under low TF activation. RESULTS: FVIII inhibitors prolonged ACTs by 2.2-fold compared to those in normal plasma mixture at baseline. During CPB, ACTs in normal plasma mixture, and FVIII-deficient mixture were in 400s, but ACTs reached 900s in FVIII-inhibitor mixture. Emicizumab shortened ACTs by up to 100s in normal plasma mixture, and FVIII-deficient mixtures. ACTs remained over 600s in FVIII-inhibitor mixture, despite adding emicizumab at 100 µg/ml. Heparin concentration measured by TF-based protamine titration was unaffected. Emicizumab enhanced thrombin peak in the presence of FVIII inhibitors, whereas plasmin generation was mainly affected by thrombin generation, and systemic use of ɛ-aminocaproic acid. CONCLUSIONS: FVIII inhibitors extensively prolong ACTs in heparinized whole blood, and clinical levels of emicizumab partially reverse ACT values. Protamine titration should be considered for optimal heparin monitoring in emicizumab-treated patients with FVIII inhibitors.

Mitral Valve Translocation: A Novel Operation for the Treatment of Secondary Mitral Regurgitation.

BACKGROUND: Conventional annuloplasty repair of secondary (functional) ischemic mitral regurgitation (IMR) is associated with a 60% recurrence of moderate or greater mitral regurgitation at 2 years. We developed a novel repair technique for IMR that addresses the underlying geometric alterations of the mitral valve apparatus and compared outcomes with those of conventional repair in a swine model. METHODS: Chronic IMR was induced by percutaneous embolization of the circumflex artery. Swine with severe IMR (median 9 weeks after infarction) underwent undersized rigid annuloplasty (n = 5) or translocation repair (n = 6). Translocation repair consisted of detaching the mitral valve en bloc at the annulus, creating a 1 cm wide frustum-shaped pericardial patch, and suturing the outer circumference of the patch to the annulus and inner circumference to the mitral valve. RESULTS: Operative survival was 92% (11 of 12). All animals had none/trace residual central mitral regurgitation, and mean inflow gradients were similar (1 mm Hg [interquartile range, 1 to 2] vs 2 mm Hg [interquartile range, 1 to 2]; P = .75) in the annuloplasty and translocation groups, respectively. Median coaptation length marginally improved in conventional swine (3 to 4 mm, P = .05), but dramatically improved in translocation swine (3 to 8 mm, P = .003). Posterior leaflet angle increased from 39 to 80 degrees (P = .05) in annuloplasty swine but decreased from 50 to 31 degrees (P = .03) in translocation swine. The posterior leaflet was immobile after annuloplasty but had preserved motion after translocation (excursion, 1 degree vs 24 degrees; P = .045). CONCLUSIONS: Mitral valve translocation effectively treats mitral regurgitation by relieving leaflet tethering. Compared with annuloplasty, mitral valve translocation creates a larger surface of coaptation and preserves leaflet mobility without compromising diastolic function.

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.

Hematologic evaluation of intraoperative autologous blood collection and allogeneic transfusion in cardiac surgery.

BACKGROUND: Acute normovolemic hemodilution is recommended as a technique to reduce allogeneic red blood cell (RBC) transfusions in cardiac surgery, but its efficacy to reduce non-RBC transfusion has not been consistently demonstrated. We hypothesized that intraoperative large-volume autologous whole blood (AWB) collection and reinfusion improves viscoelastic coagulation parameters. STUDY DESIGN AND METHODS: Prospective observational study of cardiac surgery patients at the University of Maryland Medical Center between December 2017 and August 2019. Rotational thromboelastometry parameters were compared between AWB and control groups (n = 25 in each group) at three time points: T1, baseline; T2, on cardiopulmonary bypass (CPB) after the cross-clamp removal; and T3, 30-60 minutes after protamine administration. The study's primary outcomes were whole blood viscoelastic coagulation parameters that included EXTEM clotting time (CT), FIBTEM amplitude at 10 minutes, and EXTEM amplitude at 10 minutes (EXTEM-A10 ). Chest tube drainage and allogeneic transfusion were secondary outcomes. RESULTS: Reinfusion of AWB after CPB resulted in a significantly shorter EXTEM CT; mean difference, -11.4 seconds (-21.4 to -1.4; P = .03). It also resulted in a greater percentage increase in EXTEM A10 from T2 to T3; mean difference, 7.8% (95% CI, 1.1%-14.5%; P = .02). Statistical significance was not found in 24-hour chest tube drainage. CONCLUSION: Large-volume AWB collection and reinfusion are feasible in selected cardiac surgical patients, and may be associated with prohemostatic effects according to thromboelastometry, warranting further investigation with a prospective randomized study.

Initial Clinical Experience With Mitral Valve Translocation for Secondary Mitral Regurgitation.

BACKGROUND: Functional (secondary) mitral regurgitation (FMR) results from altered geometry of the mitral valve apparatus. Repair with restrictive mitral annuloplasty is associated with high rates of recurrent mitral regurgitation (MR). We developed a novel operative repair for FMR that translocates the intact mitral valve towards the apex. METHODS: The mitral valve was detached circumferentially and translocated into the ventricle with a frustum-shaped glutaraldehyde-treated autologous pericardial patch. Clinical and echocardiographic follow-up was performed. RESULTS: Fifteen consecutive patients with FMR (mean age, 59 years; 67% female) had mitral valve translocation between 2018 and 2020. Preoperative mean ejection fraction, left ventricular end-diastolic dimension, and systolic pulmonary artery pressure were 40% ± 11%, 59 ± 8 mm, and 49 ± 21 mm Hg, respectively; 33% had atrial fibrillation. Cardiomyopathy was ischemic in 4 and nonischemic in 11. Concomitant procedures included tricuspid valve operation (n = 8), coronary artery bypass grafting (n = 4), and atrial fibrillation ablation (n = 5). Post bypass transesophageal echocardiogram demonstrated none/trace MR in all patients and mean gradient of 3 mm Hg (interquartile range, 2-4 mm Hg). Mean leaflet extent of coaptation was 14 ± 2 mm (range, 11-17 mm). There was no postoperative mortality, stroke, or renal failure. Predismissal echocardiography showed none/trace MR in 14 patients and mild MR in 1. One patient underwent successful late rerepair of a suture line leak. Twelve patients were alive at latest follow-up and MR at 1 and 6 months was mild or less in all patients with mean leaflet extent of coaptation of 14 ± 2 mm (range, 12-16 mm) at 6 months. CONCLUSIONS: Mitral valve translocation creates a large surface of coaptation and effectively corrects FMR. Further study is needed to demonstrate the long-term durability and clinical utility of this operation.

A Pharmacokinetic and Pharmacodynamic Investigation of an ε-Aminocaproic Acid Regimen Designed for Cardiac Surgery With Cardiopulmonary Bypass.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of an ε-aminocaproic acid (EACA) regimen designed for cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: Prospective observational study requiring blood sampling to measure EACA concentrations and fibrinolysis markers (fibrinogen, D-dimer, α2-antiplasmin, and tissue plasminogen activator-plasminogen activator inhibitor [tPA-PAI-1] complex). SETTING: Single-center, tertiary medical center. PARTICIPANTS: Patients who underwent cardiac surgery with CPB between 2018 and 2019 for aortic or mitral valve replacement/repair or coronary artery bypass grafting. Previous sternotomy patients were included. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of EACA, during CPB, were described by a 3-compartment disposition model. EACA concentrations were greater than 130 mg/L in all patients after CPB and in most patients during CPB. The D-dimer level trended up and reached a peak median level of 1.35 mg/L of fibrinogen equivalence units (FEU) at 15 minutes after protamine administration. The median change in D-dimer (ΔD-dimer) from baseline to 15 minutes after protamine was 0.34 (-0.48 to 3.81) mg/L FEU. ΔD-dimer did not correlate with EACA concentration intraoperatively, urine output, body weight, glomerular filtration rate, cell salvage volume, and ultrafiltration volume. The median 24-hour chest tube output was 445 (180-1,011) mL. CONCLUSION: This regimen provided maximum EACA concentrations near the time of protamine administration, with a total perioperative dose of 15 g. Most patients had EACA concentrations greater than the target during CPB. ΔD-dimer did not correlate with EACA concentration. The median 24-hour chest tube output compared well to similar studies that used higher doses of EACA.

Evolution of viscoelastic coagulation testing.

INTRODUCTION: The methods of viscoelastic coagulation testing (VCT) have evolved since the original invention of thrombelastography over 60 years ago, and new generations of devices are clinically used to guide hemostatic interventions at bedside. The utility of VCTs has been demonstrated in several clinical trials, but diagnostic performance of VCT may vary between devices, various transfusion algorithms, and patient populations. AREAS COVERED: Working principles and currently available data on the evolving VCTs for coagulation monitoring in acute care settings are reviewed. The PubMed database was used to search pertinent retrospective, prospective, and meta-analysis data on VCTs. EXPERT OPINION: Point-of-care VCTs provide clinically useful information on platelet count, fibrin polymerization, and other procoagulant factor activities in acute bleeding due to trauma or major surgery, and antithrombotic therapy. The addition of fibrin-specific VCT channel has brought renewed attention to early correction of fibrinogen deficiency using fibrinogen-rich component therapy, and stabilization of fibrin with antifibrinolytic agents. Normal reference ranges vary between devices, and diagnostic and treatment algorithms should be specifically established for each device and indication. There is interest in utilizing VCTs in complex coagulation management relating to hemophilia with inhibitors, but the standardized protocol has not been established.

Clotting Time Results Are Not Interchangeable Between EXTEM and FIBTEM on Rotational Thromboelastometry.

OBJECTIVE: To explore how cytochalasin D (CyD) affects clot initiation and to compare clotting times (CTs) of EXTEM and FIBTEM on rotational thromboelastometry in cardiac surgical patients undergoing cardiopulmonary bypass (CPB). DESIGN: Retrospective cohort study with translational in vitro coagulation experiments. SETTING: Single-center, tertiary, academic medical center. PARTICIPANTS: Patients who underwent cardiac surgery with CPB between November 2015 and August 2017. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The study's primary measurements were CTEXTEM and CTFIBTEM before and after CPB. Additionally, the authors performed translational in vitro coagulation experiments using commercial plasma. In these experiments, the impact of CyD on in vitro thrombin generation (TG) was assessed using 10 platelet-rich plasma (PRP) samples and calibrated automated thrombogram. The impact of CyD on ROTEM-CT also was evaluated in vitro using the same 10 PRP samples. One hundred fifty-three patients had clinical CTEXTEM and CTFIBTEM measurements. CTFIBTEM was shorter than CTEXTEM before and after CPB by 6.8% (95% confidence interval [CI], 5.5-8.1) and 8.9% (95% CI, 4.7-13.0), respectively. These results correlated with in vitro experiments, where TG lag time was shortened by CyD and CTFIBTEM was shorter than CTEXTEM. CONCLUSION: CyD shortens the onset of TG and clot formation, resulting in shorter CTFIBTEM than CTEXTEM. The authors' data suggest that CTEXTEM and CTFIBTEM are not interchangeable. Additional clinical studies are warranted to assess if CTFIBTEM can be used to optimize the indication for plasma transfusion.