Hypothermic oxygenated perfusion of the donor heart in heart transplantation: the short-term outcome from a randomised, controlled, open-label, multicentre clinical trial.

BACKGROUND: Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS. METHODS: We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18-70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing. FINDINGS: A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32-0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20-0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34-0·92). INTERPRETATION: Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE. FUNDING: XVIVO Perfusion.

Current Status of Cardiac Xenotransplantation: Report of a Workshop of the German Heart Transplant Centers, Martinsried, March 3, 2023.

This report comprises the contents of the presentations and following discussions of a workshop of the German Heart Transplant Centers in Martinsried, Germany on cardiac xenotransplantation. The production and current availability of genetically modified donor pigs, preservation techniques during organ harvesting, and immunosuppressive regimens in the recipient are described. Selection criteria for suitable patients and possible solutions to the problem of overgrowth of the xenotransplant are discussed. Obviously microbiological safety for the recipient and close contacts is essential, and ethical considerations to gain public acceptance for clinical applications are addressed. The first clinical trial will be regulated and supervised by the Paul-Ehrlich-Institute as the National Competent Authority for Germany, and the German Heart Transplant Centers agreed to cooperatively select the first patients for cardiac xenotransplantation.

Impact of Preoperative Functional Status on Quality of Life after Cardiac Surgery.

BACKGROUND: With increasing importance, health-related quality of life (HRQoL) has become a crucial outcome measure of cardiac surgery. The aim of this study was to assess the dynamics of HRQoL change within 12 months after surgery and to identify predictors of deterioration in physical and mental health. METHODS: The cohort of this prospective study included 164 consecutive patients who underwent elective surgery. HRQoL was assessed on the basis of the Short-Form 36 questionnaire at three different times: upon admission and at 3 and 12 months after surgery. The minimal clinically important difference (MCID) was used to determine whether the surgery resulted in deterioration of HRQoL. RESULTS: In general, physical and mental health status improved within the first year after cardiac surgery. However, after 12 months, 7.9 and 21.2% of patients had clinically significant poorer physical (PCS) and mental component summary (MCS) scores, based on the MCID approach. The results of multivariate analysis identified preoperative health status, age < 70 years, coronary artery bypass grafting, and a previous neurological event as predictors of deterioration in postoperative HRQoL. The greatest risks for deterioration were higher preoperative PCS and MCS scores. CONCLUSION: Although we were able to demonstrate a general improvement in the HRQoL following cardiac surgery, in one-fifth of patients, there was no recovery of mental health status even after 1 year. As this effect is mainly determined by preoperative functional status, HRQoL should be an integral part of medical consultation, especially in younger patients with a positive perception of quality of life.

Synchronous force and Ca2+ measurements for repeated characterization of excitation-contraction coupling in human myocardium.

Dysfunctional Ca2+ signaling affects the myocardial systole and diastole, may trigger arrhythmia and cause transcriptomic and proteomic modifications in heart failure. Thus, synchronous real-time measurement of Ca2+ and force is essential to investigate the relationship between contractility and Ca2+ signaling and the alteration of excitation-contraction coupling (ECC) in human failing myocardium. Here, we present a method for synchronized acquisition of intracellular Ca2+ and contraction force in long-term cultivated slices of human failing myocardium. Synchronous time series of contraction force and intracellular Ca2+ were used to calculate force-calcium loops and to analyze the dynamic alterations of ECC in response to various pacing frequencies, post-pause potentiation, high mechanical preload and pharmacological interventions in human failing myocardium. We provide an approach to simultaneously and repeatedly investigate alterations of contractility and Ca2+ signals in long-term cultured myocardium, which will allow detecting the effects of electrophysiological or pharmacological interventions on human myocardial ECC.

Mid-Term Outcome after Extracorporeal Life Support in Postcardiotomy Cardiogenic Shock: Recovery and Quality of Life.

Background: Extracorporeal life support (ECLS) therapy for refractory postcardiotomy cardiogenic shock (rPCS) is associated with high early mortality rates. This study aimed to identify negative predictors of mid-term survival and to assess health-related quality of life (HRQoL) and recovery of the survivors. Methods: Between 2017 and 2020, 142 consecutive patients received ECLS therapy following cardiac surgery. The median age was 66.0 [57.0-73.0] years, 67.6% were male and the median EuroSCORE II was 10.5% [4.2-21.3]. In 48 patients, HRQoL was examined using the 36-Item Short Form Survey (SF-36) and the modified Rankin-Scale (mRS) at a median follow-up time of 2.2 [1.9-3.2] years. Results: Estimated survival rates at 3, 12, 24 and 36 months were 47%, 46%, 43% and 43% (SE: 4%). Multivariable Cox Proportional Hazard regression analysis revealed preoperative EuroSCORE II (p = 0.013), impaired renal function (p = 0.010), cardiopulmonary bypass duration (p = 0.015) and pre-ECLS lactate levels (p = 0.004) as independent predictors of mid-term mortality. At the time of follow-up, 83.3% of the survivors were free of moderate to severe disability (mRS < 3). SF-36 analysis showed a physical component summary of 45.5 ± 10.2 and a mental component summary of 50.6 ± 12.5. Conclusions: Considering the disease to be treated, ECLS for rPCS is associated with acceptable mid-term survival, health-related quality of life and functional status. Preoperative EuroSCORE II, impaired renal function, cardiopulmonary bypass duration and lactate levels prior to ECLS implantation were identified as negative predictors and should be included in the decision-making process.

[Thrombotic microangiopathies in surgical intensive care medicine with special consideration of atypical hemolytic uremic syndrome]. / Thrombotische Mikroangiopathien in der operativen Intensivmedizin unter besonderer Berücksichtigung des atypischen hämolytisch-urämischen Syndroms.

Thrombotic microangiopathies (TMA) are rare diseases, which are defined by the triad microangiopathic hemolytic anemia, thrombocytopenia and organ damage, and are associated with high morbidity and mortality. The recognition of a TMA and the distinction of important differential diagnoses are key factors, particularly in a perioperative context and in routine clinical intensive care. The further differentiation of the different TMA subtypes, such as thrombotic thrombocytopenic purpura (TTP), Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) and atypical hemolytic uremic syndrome (aHUS), based on the underlying pathophysiology and the development of new targeted treatment options in recent years have significantly improved the prognosis. A close interdisciplinary cooperation between critical care specialists and specialist disciplines experienced in the treatment of TMA, is essential for a prompt diagnosis and the initiation of the appropriate treatment.

A novel intrapericardial pulsatile device for individualized, biventricular circulatory support without direct blood contact.

OBJECTIVE: Due to severely limited donor heart availability, durable mechanical circulatory support remains the only treatment option for many patients with end-stage heart failure. However, treatment complexity persists due to its univentricular support modality and continuous contact with blood. We investigated the function and safety of reBEAT (AdjuCor GmbH), a novel, minimal invasive mechanical circulatory support device that completely avoids blood contact and provides pulsatile, biventricular support. METHODS: For each animal tested, an accurately sized cardiac implant was manufactured from computed tomography scan analyses. The implant consists of a cardiac sleeve with three inflatable cushions, 6 epicardial electrodes and driveline connecting to an electro-pneumatic, extracorporeal portable driver. Continuous epicardial electrocardiogram signal analysis allows for systolic and diastolic synchronization of biventricular mechanical support. In 7 pigs (weight, 50-80 kg), data were analyzed acutely (under beta-blockade, n = 5) and in a 30-day long-term survival model (n = 2). Acquisition of intracardiac pressures and aortic and pulmonary flow data were used to determine left ventricle and right ventricle stroke work and stroke volume, respectively. RESULTS: Each implant was successfully positioned around the ventricles. Automatic algorithm electrocardiogram signal annotations resulted in precise, real-time mechanical support synchronization with each cardiac cycle. Consequently, progressive improvements in cardiac hemodynamic parameters in acute animals were achieved. Long-term survival demonstrated safe device integration, and clear and stable electrocardiogram signal detection over time. CONCLUSIONS: The present study demonstrates biventricular cardiac support with reBEAT. Various demonstrated features are essential for realistic translation into the clinical setting, including safe implantation, anatomical fit, safe device-tissue integration, and real-time electrocardiogram synchronized mechanical support, result in effective device function and long-term safety.

Case report: Central venous catheter thrombosis complicated by chronic thromboembolic disease/pulmonary hypertension in two children requiring parenteral nutrition.

Chronic thromboembolic pulmonary hypertension is a rare but life-threatening complication of long-term central venous catheters (CVC) in children. However, evidence in terms of potential treatment strategies and outcome data remains scarce. We describe two cases of CVC-related thrombosis (Hickman-catheter) complicated by recurrent pulmonary emboli. One patient experienced a complete thromboembolic obstruction of the right pulmonary artery with normal pulmonary pressures and the second patient suffered from a central thromboembolic obstruction of both pulmonary arteries associated with severe pulmonary hypertension. Both patients successfully underwent surgical thromboendarterectomy with deep hypothermic circulatory arrest.

Case report: Paracorporeal lung assist device for 215 days as a bridge-to-lung transplantation in a patient with bronchopulmonary dysplasia and severe pulmonary hypertension.

Pulmonary hypertension (PH) is a known and life limiting complication of preterm born young adults with bronchopulmonary dysplasia (BPD), ultimately leading to progressive right ventricular (RV) failure. Prognosis remains poor, especially in patients unresponsive to modern vasoactive pharmacotherapy. Therefore, lung transplantation presents the treatment of choice to avert cardiac failure. With limited donor organ availability and long waiting times, the implantation of a paracorporeal lung assist device (PLAD) is a way to bridge the patient as an alternative to veno-arterial ECMO. Herein, we present the case of a prematurely born 23-year-old female, who developed severe PH due to BPD and consequently experienced therapy refractory RV failure. Urgent PLAD implantation was performed and the patient successfully underwent double-lung transplantation after 215 days of PLAD support. No major PLAD-associated complications occurred and full recovery of RV function could be observed after double-lung transplantation.

Interdisciplinary Management of the Emergency Treatment in an Atrioesophageal Fistula.

The atrioesophageal fistula is a fulminant complication of radiofrequency ablation in atrial fibrillation, with a mortality as high as 80%. Surgical approaches have been insufficiently dealt with in literature. Treating a 42-year-old male patient, we developed an interdisciplinary two-step concept: (1) resection of the affected third of the esophagus and closing of the atrial defect using cardiopulmonary bypass and cardioplegic cardiac arrest; and (2) a second surgery to restore gastrointestinal continuity after an adequate term. Our patient has fully recovered.

Thrombotic microangiopathy following aortic surgery with hypothermic circulatory arrest: a single-centre experience of an underestimated cause of acute renal failure.

OBJECTIVES: Acute kidney injury (AKI) following surgery involving the heart-lung-machine is associated with high mortality and morbidity. In addition to the known mechanisms, thrombotic microangiopathy (TMA) triggered by the dysregulation of complement activation was recently described as another pathophysiological pathway for AKI following aortic surgery. The aim of this retrospective study was to analyse incidence, predictors and outcome in these patients. METHODS: Between January 2018 and September 2019, consecutive patients undergoing aortic surgery requiring hypothermic circulatory arrest were retrospectively reviewed. If suspected, diagnostic algorithm was initiated to identify a TMA and its risk factors, and postoperative outcome parameters were comparably investigated. RESULTS: The incidence of TMA in the analysed cohort (n = 247) was 4.5%. Multivariable logistic regression indicated female gender {odds ratio (OR) 4.905 [95% confidence interval (CI) 1.234-19.495], P = 0.024} and aortic valve replacement [OR 8.886 (95% CI 1.030-76.660), P = 0.047] as independent predictors of TMA, while cardiopulmonary bypass, X-clamp and hypothermic circulatory arrest times showed no statistically significance. TMA resulted in postoperative AKI (82%), neurological disorders (73%) and thrombocytopaenia [31 (interquartile range 25-42) G/l], corresponding to the diagnostic criteria. Operative mortality and morbidity were equal to patients without postoperative TMA, despite a higher incidence of re-exploration for bleeding (27 vs 6%; P = 0.027). After 6 months, survival, laboratory parameters and need for dialysis were comparable between the groups. CONCLUSIONS: TMA is a potential differential diagnosis for the cause of AKI following aortic surgery regardless of the hypothermic circulatory arrest time. Timely diagnosis and appropriate treatment resulted in a comparable outcome concerning mortality and renal function.

Case report: Heart Mate III for systemic right ventricular support in a patient with hypoplastic left heart syndrome.

Ventricular assist device implantation presents a possible bridge to heart transplantation for patients with failing Fontan physiology. However, evidence regarding outcome and possible pitfalls associated with the Fontan circulation is still insufficient. We describe the course of a 13-year-old male, who was born with hypoplastic left heart syndrome and underwent HeartMate III implantation due to refractory failure of the systemic right ventricle.

Atrio-aortic erosion caused by Amplatzer Atrial Septal Occluder - a case report.

BACKGROUND: In specialized centers, percutaneous closure using specific occluders is the first-choice treatment in atrial septal defects (ASD). Late complications after this intervention, such as erosion of the aorta or the atria, are rare and have not been sufficiently approached and dealt with in literature. In our clinic we have been faced with the problematic situation of diagnosing and treating such cases. That is why, we have decided to share our experience with other colleagues. CASE PRESENTATION: We present two cases of severe late complications after percutaneous closure of atrial septal defects (ASD). In both cases, the atrial septal occluder (Amplatzer™ Atrial Septal Occluder Device, Abbott, Chicago USA) caused the erosion between the left atrium and the aortic root. The atrio-aortic erosion led to acute cardiac tamponade with upper venous congestion and shock. As the bleeding source remained undetectable for any imaging tools, a diagnostical sternotomy remained the only solution. The cause of the acute bleeding was discovered to be the erosion between the left atrium and the aortic root. The treatment consisted in the removal of the occluder, direct suturing of the perforated areas and the surgical closure of the remaining ASD. The patients fully recovered within the nine to fourteen days' hospital stay. Six months after surgery both patients were well and able to recover their daily routine. CONCLUSIONS: The atrio-aortic erosion after percutaneous closure of atrial septal defects is a surgical emergency. The more so, since it can be complicated by the absence of specific symptoms. A key-element in the diagnosis of this rare pathology remains the medical history of the patient, which the surgeon has to consider thoroughly and launch the diagnostic sternotomy without delay.

Severe Acute Kidney Injury in Cardiovascular Surgery: Thrombotic Microangiopathy as a Differential Diagnosis to Ischemia Reperfusion Injury. A Retrospective Study.

BACKGROUND: Acute kidney injury (AKI) after cardiovascular surgery (CVS) infers high morbidity and mortality and may be caused by thrombotic microangiopathy (TMA). This study aimed to assess incidence, risk factors, kidney function, and mortality of patients with a postoperative TMA as possible cause of severe AKI following cardiovascular surgery. METHODS: We analyzed retrospectively all patients admitted to the ICU after a cardiovascular procedure between 01/2018 and 03/2019 with severe AKI and need for renal replacement therapy (RRT). TMA was defined as post-surgery-AKI including need for RRT, hemolytic anemia, and thrombocytopenia. TMA patients were compared to patients with AKI requiring RRT without TMA. RESULTS: Out of 893 patients, 69 (7.7%) needed RRT within one week after surgery due to severe AKI. Among those, 15 (21.7%) fulfilled TMA criteria. Aortic surgery suggested an increased risk for TMA (9/15 (60.0%) vs. 7/54 (31.5%), OR 3.26, CI 1.0013-10.64). Ten TMA patients required plasmapheresis and/or eculizumab, and five recovered spontaneously. Preoperative kidney function was significantly better in TMA patients than in controls (eGFR 92 vs. 60.5 mL/min, p = 0.004). However, postoperative TMA resulted in a more pronounced GFR loss (ΔeGFR -54 vs. -17 mL/min, p = 0.062). There were no deaths in the TMA group. CONCLUSION: Our findings suggest TMA as an important differential diagnosis of severe AKI following cardiovascular surgery, which may be triggered by aortic surgery. Therefore, early diagnosis and timely treatment of TMA could reduce kidney damage and improve mortality of AKI following cardiovascular surgery, which should be further investigated.