Ex Situ Left Ventricular Pressure-Volume Loop Analyses for Donor Hearts: Proof of Concept in an Ovine Experimental Model.

Ex situ heart perfusion (ESHP) has emerged as an important strategy to preserve donation after brain death (DBD) and donation after circulatory death (DCD) donor hearts. Clinically, both DBD and DCD hearts are successfully preserved using ESHP. Viability assessment is currently based on biochemical values, while a reliable method for graft function assessment in a physiologic working mode is unavailable. As functional assessment during ESHP has demonstrated the highest predictive value of outcome post-transplantation, this is an important area for improvement. In this study, a novel method for ex situ assessment of left ventricular function with pressure-volume loop analyses is evaluated. Ovine hearts were functionally evaluated during normothermic ESHP with the novel pressure-volume loop system. This system provides an afterload and adjustable preload to the left ventricle. By increasing the preload and measuring end-systolic elastance, the system could successfully assess the left ventricular function. End-systolic elastance at 60 min and 120 min was 2.8 ± 1.8 mmHg/mL and 2.7 ± 0.7 mmHg/mL, respectively. In this study we show a novel method for functional graft assessment with ex situ pressure-loop analyses during ESHP. When further validated, this method for pressure-volume assessments, could be used for better graft selection in both DBD and DCD donor hearts.

Three Decades Single Center Experience of Airway Complications After Lung Transplantation.

Post lung transplantation airway complications like necrosis, stenosis, malacia and dehiscence cause significant morbidity, and are most likely caused by post-operative hypo perfusion of the anastomosis. Treatment can be challenging, and airway stent placement can be necessary in severe cases. Risk factors for development of airway complications vary between studies. In this single center retrospective cohort study, all lung transplant recipients between November 1990 and September 2020 were analyzed and clinically relevant airway complications of the anastomosis or distal airways were identified and scored according to the ISHLT grading system. We studied potential risk factors for development of airway complications and evaluated the impact on survival. The treatment modalities were described. In 651 patients with 1,191 airway anastomoses, 63 patients developed 76 clinically relevant airway complications of the airway anastomoses or distal airways leading to an incidence of 6.4% of all anastomoses, mainly consisting of airway stenosis (67%). Development of airway complications significantly affects median survival in post lung transplant patients compared to patients without airway complication (101 months versus 136 months, p = 0.044). No significant risk factors for development of airway complication could be identified. Previously described risk factors could not be confirmed. Airway stents were required in 55% of the affected patients. Median survival is impaired by airway complications after lung transplantation. In our cohort, no significant risk factors for the development of airway complications could be identified.

Listing criteria for heart transplantation in the Netherlands.

The updated listing criteria for heart transplantation are presented on behalf of the three heart transplant centres in the Netherlands. Given the shortage of donor hearts, selection of those patients who may expect to have the greatest benefit from a scarce societal resource in terms of life expectancy and quality of life is inevitable. The indication for heart transplantation includes end-stage heart disease not remediable by more conservative measures, accompanied by severe physical limitation while on optimal medical therapy, including ICD/CRT­D. Assessment of this condition requires cardiopulmonary stress testing, prognostic stratification and invasive haemodynamic measurements. Timely referral to a tertiary centre is essential for an optimal outcome. Chronic mechanical circulatory support is being used more and more as an alternative to heart transplantation and to bridge the progressively longer waiting time for heart transplantation and, thus, has become an important treatment option for patients with advanced heart failure.

Waiting list mortality and the potential of donation after circulatory death heart transplantations in the Netherlands.

BACKGROUND: With more patients qualifying for heart transplantation (HT) and fewer hearts being transplanted, it is vital to look for other options. To date, only organs from brain-dead donors have been used for HT in the Netherlands. We investigated waiting list mortality in all Dutch HT centres and the potential of donation after circulatory death (DCD) HT in the Netherlands. METHODS: Two different cohorts were evaluated. One cohort was defined as patients who were newly listed or were already on the waiting list for HT between January 2013 and December 2017. Follow-up continued until September 2018 and waiting list mortality was calculated. A second cohort of all DCD donors in the Netherlands (lung, liver, kidney and pancreas) between January 2013 and December 2017 was used to calculate the potential of DCD HT. RESULTS: Out of 395 patients on the waiting list for HT, 196 (50%) received transplants after a median waiting time of 2.6 years. In total, 15% died while on the waiting list before a suitable donor heart became available. We identified 1006 DCD donors. After applying exclusion criteria and an age limit of 50 years, 122 potential heart donors remained. This number increased to 220 when the age limit was extended to 57 years. CONCLUSION: Waiting list mortality in the Netherlands is high. HT using organs from DCD donors has great potential in the Netherlands and could lead to a reduction in waiting list mortality. Cardiac screening will eventually determine the true potential.

Distribution of perioperative stroke in cardiac surgery.

BACKGROUND AND PURPOSE: The recent literature suggests that a cardiac origin in ischaemic stroke is more frequent than previously assumed. However, it is not always clear which patients benefit from additional cardiac investigations if obvious cardiac pathology is absent. METHODS: A single-center retrospective observational study was performed with 7454 consecutive patients admitted to the intensive care unit after cardiac surgery in the period 2006-2015 and who had postoperative brain imaging. Cerebral imaging was studied for the occurrence of stroke including subtype and involved vascular territory. It was assumed that all perioperative thromboembolic strokes are of cardiac origin. Data obtained from a hospital cohort of consecutive patients who received a diagnosis of ischaemic stroke were used for comparison. RESULTS: Thromboembolic stroke occurred in 135 cardiac surgery patients in 56 (41%) of whom the posterior cerebral circulation was involved. In the control group, 100 out of 503 strokes (20%) were located in the posterior cerebral circulation. The relative risk for a posterior location for stroke after cardiac surgery compared to patients with ischaemic stroke without prior cardiac surgery was 2.09; 95% confidence interval 1.60-2.72. CONCLUSIONS: Thromboembolic stroke after cardiac surgery occurs twice as often in the posterior cerebral circulation compared to ischaemic strokes in the general population. If confirmed in general stroke cohorts, the consequence of this finding may be that in patients with an ischaemic stroke that involves the posterior cerebral circulation the chance of a cardiac origin is increased and therefore might trigger additional cardiac investigations such as long-term heart rhythm monitoring or echocardiography.

Patient-reported health outcomes in long-term lung transplantation survivors: A prospective cohort study.

During the last three decades lung transplantation (LTx) has become a proven modality for increasing both survival and health-related quality of life (HRQoL) in patients with various end-stage lung diseases. Most previous studies have reported improved HRQoL shortly after LTx. With regard to long-term effects on HRQoL, however, the evidence is less solid. This prospective cohort study was started with 828 patients who were on the waiting list for LTx. Then, in a longitudinal follow-up, 370 post-LTx patients were evaluated annually for up to 15 years. For all wait-listed and follow-up patients, the following four HRQoL instruments were administered: State-Trait Anxiety Inventory, Zung Self-rating Depression Scale, Nottingham Health Profile, and a visual analogue scale. Cross-sectional and generalized estimating equation (GEE) analysis for repeated measures were performed to assess changes in HRQoL during follow-up. After LTx, patients showed improvement in all HRQoL domains except pain, which remained steady throughout the long-term follow-up. The level of anxiety and depressive symptoms decreased significantly and remained constant. In conclusion, this study showed that HRQoL improves after LTx and tends to remain relatively constant for the entire life span.

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool.

The diagnosis of left ventricular assist device thrombosis.

The clinical course of a patient with a left ventricular assist device is described. A total of 6 weeks after device insertion, the lactate dehydrogenase (LDH) level increased to 2801 U/l despite adding low-molecular-weight heparin to acenocoumarol and aspirin. Pump thrombosis was suspected but unconfirmed by computed tomography. Increased pump power requirement did not occur. Instituting unfractionated heparin caused a drop in the LDH level. After discontinuing heparin, the LDH levels rose to 5529 U/l whereupon pump replacement was performed. LDH levels, combined with clinical deterioration and right heart catheterisation, led to the diagnosis of pump thrombosis.

Development of a Hyperactive Primary Hemostatic System During Off-Pump Lung Transplantation Resulting From an Unbalance Between von Willebrand Factor and Its Cleaving Protease ADAMTS13.

An unbalance between the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 is a risk factor for thrombosis. Here, we assessed levels and functionality of VWF and ADAMTS13 in patients undergoing off-pump lung transplantation. We analyzed plasma of 10 patients and distinguished lung transplantation-specific effects from those generally accompanying open-chest surgeries by comparing results with 11 patients undergoing off-pump coronary bypass graft (CABG) surgery. Forty healthy volunteers were included for reference values. VWF antigen levels as well as the VWF ristocetin cofactor activity/VWF antigen ratio increased during lung transplantation and after CABG surgery. An increase in VWF propeptide levels was paralleled by a decrease in ADAMTS13 activity. This was more pronounced during lung transplantation. Similarly, the capacity of plasma to support platelet aggregation under shear flow conditions in vitro was more increased during lung transplantation. The proportion of high molecular weight VWF multimers was elevated in both groups without evidence for ultra-large VWF. VWF's collagen binding activity remained unchanged. In conclusion, a hyperactive primary hemostatic system develops during lung transplantation resulting both from a pronounced (functional) increase of the VWF molecule and decrease of ADAMTS13. This may increase the risk of platelet thrombosis within the allograft.

Former smoking is a risk factor for chronic kidney disease after lung transplantation.

Chronic kidney disease (CKD) is a common complication after lung transplantation (LTx). Smoking is a risk factor for many diseases, including CKD. Smoking cessation for >6 months is required for LTx enlistment. However, the impact of smoking history on CKD development after LTx remains unclear. We investigated the effect of former smoking on CKD and mortality after LTx. CKD was based on glomerular filtration rate (GFR) ((125) I-iothalamate measurements). GFR was measured before and repeatedly after LTx. One hundred thirty-four patients never smoked and 192 patients previously smoked for a median of 17.5 pack years. At 5 years after LTx, overall cumulative incidences of CKD-III, CKD-IV and death were 68.5%, 16.3% and 34.6%, respectively. Compared to never smokers, former smokers had a higher risk for CKD-III (hazard ratio [HR] 95% confidence interval [95%CI]= 1.69 [1.27-2.24]) and IV (HR = 1.90 [1.11-3.27]), but not for mortality (HR = 0.99 [0.71-1.38]). Adjustment for potential confounders did not change results. Thus, despite cessation, smoking history remained a risk factor for CKD in LTx recipients. Considering the increasing acceptance for LTx of older recipients with lower baseline renal function and an extensive smoking history, our data suggest that the problem of post-LTx CKD may increase in the future.

Apoptosis during CABG surgery with the use of cardiopulmonary bypass is prominent in ventricular but not in atrial myocardium.

Objectives. We aimed to compare the rate of apoptosis after cardiopulmonary bypass (CPB) and cardioplegic arrest during coronary artery bypass grafting (CABG) surgery between atrial and ventricular tissue.Methods. During CABG surgery with CPB and cardioplegic arrest, sequential biopsies were taken from the right atrial appendage and left ventricular anterior wall before CPB and after aortic cross clamp release. Change in number of apoptotic cells and biochemical markers of myocardial ischaemia and renal dysfunction were assessed.Results. CPB was associated with a transient small, but significant increase in CK (1091+/-374%), CK-MB (128+/-38%), troponin-T (102+/-13%) and NT-proBNP (1308+/-372%) levels (all: p<0.05). A higher number of apoptotic cells as assessed by caspase-3 staining was found in the ventricular biopsies taken after aortic cross clamp release compared with the biopsies taken before CPB (5.3+/-0.6 vs. 14.0+/-1.5 cells/microscopic field, p<0.01). The number of apoptotic cells in the atrial appendage was not altered during CPB. Correlation between the duration of aortic cross clamp time and the change in caspase-3 positive cells in the left ventricular wall was of borderline significance (r of 0.58, p=0.08). Similar results were obtained from TUNEL staining for apoptosis.Conclusion. CABG surgery with CPB and cardioplegic arrest is associated with an elevated rate of apoptosis in ventricular but not in atrial myocardial tissue. Ventricular tissue may be more sensitive to detect changes than atrial tissue, and may be more useful to investigate the protective effects of therapeutic intervention. (Neth Heart J 2010;18:236-42.).

Guidelines for heart transplantation.

Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT).THE INDICATION FOR HEART TRANSPLANTATION IS DEFINED AS: 'End-stage heart disease not remediable by more conservative measures'.CONTRAINDICATIONS ARE: irreversible pulmonary hypertension/elevated pulmonary vascular resistance; active systemic infection; active malignancy or history of malignancy with probability of recurrence; inability to comply with complex medical regimen; severe peripheral or cerebrovascular disease and irreversible dysfunction of another organ, including diseases that may limit prognosis after heart transplantation.Considering the difficulties in defining end-stage heart failure, estimating prognosis in the individual patient and the continuing evolution of available therapies, the present criteria are broadly defined. The final acceptance is done by the transplant team which has extensive knowledge of the treatment of patients with advanced heart failure on the one hand and thorough experience with heart transplantation and mechanical circulatory support on the other hand. (Neth Heart J 2008;16:79-87.).

Aortic dissection presenting as acute myocardial infarction: potential harm of antithrombin and antiplatelet therapy.

In the treatment of acute myocardial infarction, antithrombin and antiplatelet therapy are indicated according to the current guidelines. When a patient presents with symptoms and signs of acute myocardial infarction, an extensive list of diagnoses should be considered. Because of the nonspecific symptoms of aortic dissection, the disease may be easily misdiagnosed. A high clinical suspicion of aortic dissection is therefore required. Once aortic dissection has been diagnosed, surgical intervention provides the only definitive treatment for these patients, regardless of antithrombin and antiplatelet therapy.

Copper, manganese, cobalt and selenium concentrations in liver samples from African buffalo (Syncerus caffer) in the Kruger National Park.

Animals may act as bio-indicators for the pollution of soil, air and water. In order to monitor changes over time, a baseline status should be established for a particular species in a particular area. The concentration of minerals in soil is a poor indicator of mineral uptake by plants and thus their availability to animals. The chemical composition of body tissue, particularly the liver, is a better reflection of the dietary status of domestic and wild animals. Normal values for copper, manganese and cobalt in the liver have been established for cattle but not for African buffalo. As part of the bovine tuberculosis (BTB) monitoring programme in the Kruger National Park (KNP) in South Africa, 660 buffalo were culled. Livers (n = 311) were randomly sampled in buffered formalin for mineral analysis. The highest concentrations of copper were measured in the northern and central parts of the KNP, which is downwind of mining and refining activities. Manganese, cobalt and selenium levels in liver samples indicated neither excess nor deficiency; however, there were some significant area, age and gender differences. The results will be useful as a baseline reference when monitoring variations in the level and extent of mineral pollution on natural pastures close to mines and refineries.

Effects of early surfactant treatment persisting for one week after lung transplantation in rats.

We investigated whether pulmonary surfactant in rat lung transplants recovered during the first week post-transplantation, along with symptoms of the reimplantation response, and whether this recovery was affected by early surfactant treatment. The severity of pulmonary injury was varied by transplanting left lungs with 6-h and 20-h ischemia (n = 12 and 19, respectively). Half of the transplants were treated by instillation of surfactant before reperfusion. Lungs from sham operated, and normal rats (n = 4 and 5, respectively) served as controls. The pulmonary injury severely impaired lung transplant function; 10 of the worst affected animals died. After 1 wk, symptoms of reimplantation response and properties of pulmonary surfactant were assessed. If untreated, the reimplantation response had almost resolved in the 6-h but not in the 20-h ischemia group; pulmonary surfactant, however, continued to be deficient in both ischemia groups (low amounts of surfactant phospholipids and surfactant protein A [SP-A]). Surfactant treatment improved the recovery from injury in the 20-h ischemia group resulting in normal lung function and amounts of surfactant phospholipids. Amounts of SP-A were not improved by surfactant treatment. In conclusion, early surfactant treatment enhances recovery from transplantation injury and is persistently beneficial for pulmonary surfactant in lung transplants.

Surfactant treatment before reperfusion improves the immediate function of lung transplants in rats.

An impaired function of alveolar surfactant can cause lung transplant dysfunction early after reperfusion. In this study it was investigated whether treatment with surfactant before reperfusion improves the immediate function of lung transplants and whether an improved transplant function was associated with an increase in alveolar surfactant components. Left lungs with 6-h (n = 8) or prolonged 20-h ischemia (n = 10) were transplanted syngeneically in rats. In both ischemia groups half of the lung transplants were treated with surfactant just before reperfusion. Lung function was measured during reperfusion for 1 h. Thereafter, the rats were killed and bronchoalveolar lavage was performed to measure alveolar surfactant components. We found that surfactant treatment improved the immediate function of lung transplants in parallel with a higher amount of total surfactant phospholipids, a higher percentage of the heavy subtype of surfactant, a normalized percentage of phosphatidylcholine, and a higher amount of endogenous surfactant protein A (SP-A). We conclude that surfactant treatment before reperfusion does improve the immediate lung transplant function in rats in association with an increase in alveolar surfactant components. More particularly, the amount of (endogenous) SP-A is thought to be crucial for the efficacy of surfactant treatment after lung transplantation.

Decision making for the surgical management of aortic coarctation associated with ventricular septal defect.

Coarctation of the aorta and associated ventricular septal defect may be repaired simultaneously or by initial coarctation repair with or without banding of the pulmonary artery. The question is whether specific preoperative criteria can enable the surgeon to choose the optimal surgical management. Between 1980 and 1993, 80 infants younger than 3 months with coarctation and ventricular septal defect were treated surgically. In 64 infants (multistage group), simple coarctation repair was performed through a posterolateral approach, with concomitant banding of the pulmonary artery in 10 infants. Twenty ventricular septal defects were closed as a secondary procedure and four were closed as a tertiary procedure. Sixteen infants (single-stage group) underwent one-stage repair through an anterior midline approach. The total in-hospital mortality rate was 7.5%. Freedom from recoarctation after 5 years was 91.3% in the multistage group versus 60.0% in the single-stage group (p = 0.018). Freedom from secondary ventricular septal defect treatment in the multistage group after 5 years was 40.7%, versus 100% in the single-stage group (p = 0.016). Thirty-seven ventricular septal defects (47.8%) closed spontaneously. In particular, the preoperative left-to-right shunt and extension of the perimembranous VSD into the inlet or outlet were risk factors for the need for eventual surgical ventricular septal defect closure after initial coarctation repair. On the basis of these two risk factors, the probability of the need for eventual surgical treatment of ventricular septal defect after initial coarctation repair can be calculated. This policy offers a well-considered choice between single-stage and multistage repair, weighing the risk of secondary ventricular septal defect treatment versus the risk of recoarctation. Finally, the number of surgical procedures per infant will be as low as possible.

The function of surfactant is impaired during the reimplantation response in rat lung transplants.

In this study we investigated the surfactant function in rat lung transplants at the peak of the reimplantation response in experimental groups with increasing warm ischemic times of the lung transplant. The left and right lungs in five groups of rats were assessed 24 hours after left lung transplantation: rats receiving transplants with lung graft ischemic times of 60 (n = 4), 90 (n = 5), and 120 (n = 5) minutes, donor rats with 120 minutes lung ischemia (n = 5) and normal (nonoperated) rats (n = 6). The reimplantation response was assessed by the ventilation score on chest roentgenograms, measurement of the static lung compliance, and the (serum) protein concentration in the bronchoalveolar lavage fluid. Surfactant in the bronchoalveolar lavage fluid was assessed by measuring the amount and the composition of surfactant phospholipids and the in vitro surfactant function in a pulsating bubble surfactometer. We found that longer ischemic times caused a more severe reimplantation response in the left lung grafts. Although the ventilation scores were equally low in the 60-, 90-, and 120-minute ischemia groups, the lung compliances decreased and the (serum) protein concentrations increased stepwise in correlation with longer ischemic times. The amount of surfactant phospholipids during the reimplantation response was not changed, but the percentage phosphatidyl choline decreased progressively in parallel with the severity of the reimplantation response. Finally, the in vitro function of surfactant from the lung transplants decreased in parallel with the prolongation of the ischemic time, whereas the function of surfactant from donor lungs with 120 minutes of ischemia and from native right lungs was not changed. We conclude that the surfactant function is impaired during the reimplantation response as a result of a high concentration of inhibiting serum proteins and a low percentage of phosphatidyl choline.