Comparison of Different Ex-Vivo Preservation Strategies on Cardiac Metabolism in an Animal Model of Donation after Circulatory Death.

Transplantation of heart following donation after circulatory death (DCD) was recently introduced into clinical practice. Ex vivo reperfusion following DCD and retrieval is deemed necessary in order to evaluate the recovery of cardiac viability after the period of warm ischemia. We tested the effect of four different temperatures (4 °C-18 °C-25 °C-35 °C) on cardiac metabolism during 3-h ex vivo reperfusion in a porcine model of DCD heart. We observed a steep fall in high-energy phosphate (ATP) concentrations in the myocardial tissue at the end of the warm ischemic time and only limited regeneration during reperfusion. Lactate concentration in the perfusate increased rapidly during the first hour of reperfusion and slowly decreased afterward. However, the temperature of the solution does not seem to have an effect on either ATP or lactate concentration. Furthermore, all cardiac allografts showed a significant weight increase due to cardiac edema, regardless of the temperature.

Significance of HLA-matching and anti-HLA antibodies in heart transplant patients receiving induction therapy?

OBJECTIVES: Though Human Leukocyte Antigen (HLA) matching benefits are demonstrated in renal transplantation, evidence in heart transplantation is lacking, and its clinical feasibility is uncertain. Post-transplantation anti-HLA antibodies are being increasingly studied in organ transplantation, with diverging conclusions between transplantated organs. METHODS: We analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, acute rejection and chronic allograft vasculopathy in 309 patients receiving induction therapy and triple-drug immunosuppression. RESULTS: The average number of HLA-A/B/DR mismatches between donor and recipient was 4.9 ± 1. The majority of mismatches was for Class I HLA-A/B with an average of 3.3, then for Class I HLA-DR with an average of 1.6. Overall, the HLA-A/-B/-DR mismatches had no influence on the cardiac allograft survival (p = 0.28). However, HLA-DR mismatches were negatively correlated to severe cellular and/or humoral allograft rejection (p = 0.04). Our analysis found anti-HLA antibodies in 27% of recipients, de novo anti-HLA antibodies in 16% of recipients, and donor-specific anti-HLA (DSA) antibodies in 8% of recipients. Furthermore, de novo DSA had no influence on the 5-year survival (78% with DSA vs. 92% without DSA; p = 0.49), which may be masked by the limited number of recipients in analysis By univariable analysis, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on severe cellular and/or humoral rejection or on chronic allograft vasculopathy. CONCLUSIONS: HLA-DR mismatch was negatively correlated to severe cellular and/or humoral allograft rejection but had no influence on cardiac allograft survival. In this study, anti-HLA antibodies (preexisting or de novo) unrelated or related to the donor had no influence on cellular and/or humoral rejection or on chronic allograft vasculopathy. The results of this study add to the controversy on the impact of allo-antibodies in heart transplant recipients receiving induction therapy and contemporary immunosuppression.

Study design and rationale of the pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R).

AIM: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF. METHODS AND RESULTS: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment. CONCLUSION: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure.

Symptomatic Val122del mutated hereditary transthyretin amyloidosis: Need for early diagnosis and prioritization for heart and liver transplantation.

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disease linked to transthyretin gene mutations which cause instability of the transthyretin tetramer. After dissociation and misfolding they reassemble as insoluble fibrils (i.e. amyloid). Apart from the common Val30Met mutation there is a very heterogeneous group of non-Val30Met mutations. In some cases, the clinical picture is dominated by a rapidly evolving restrictive and hypertrophic cardiomyopathy. METHODS: A case series of four liver recipients with the highly clinically relevant, rare and particularly aggressive Val122del mutation is presented. Medical and surgical therapeutic options, waiting list policy for ATTRv-amyloidosis, including the need for heart transplantation, and status of heart-liver transplantation are discussed. RESULTS: Three patients needed a staged (1 patient) or simultaneous (2 patients) heart-liver transplant due to rapidly progressing cardiac failure and/or neurologic disability. Domino liver transplantation was impossible in two due to fibrotic hepatic transformation caused by cardiomyopathy. After a follow-up ranging from 3.5 to 9.5 years, cardiac (allograft) function was maintained in all patients, but neuropathy progressed in three patients, one of whom died after 80 months. CONCLUSIONS: This is the first report in (liver) transplant literature about the rare Val122del ATTRv mutation. Due to its aggressiveness, symptomatic patients should be prioritized on the liver and, in cases with cardiomyopathy, heart waiting lists in order to avoid the irreversible neurological and cardiac damage that leads to a rapid lethal outcome.

Impact of COVID-19-related public containment measures on the ST elevation myocardial infarction epidemic in Belgium: a nationwide, serial, cross-sectional study.

AIMS: The current study assessed the impact of COVID-19-related public containment measures (i.e. lockdown) on the ST elevation myocardial infarction (STEMI) epidemic in Belgium. METHODS AND RESULTS: Clinical characteristics, reperfusion therapy modalities, COVID-19 status and in-hospital mortality of consecutive STEMI patients who were admitted to Belgian hospitals for percutaneous coronary intervention (PCI) were recorded during a three-week period starting at the beginning of the lockdown period on 13 March 2020. Similar data were collected for the same time period for 2017-2019. An evaluation of air quality revealed a 32% decrease in ambient NO2 concentrations during lockdown (19.5 µg/m³ versus 13.2 µg/m³, p < .001). During the three-week period, there were 188 STEMI patients admitted for PCI during the lockdown versus an average 254 STEMI patients before the lockdown period (incidence rate ratio = 0.74, p = .001). Reperfusion strategy was predominantly primary PCI in both time periods (96% versus 95%). However, there was a significant delay in treatment during the lockdown period, with more late presentations (>12 h after onset of pain) (14% versus 7.6%, p = .04) and with longer door-to-balloon times (median of 45 versus 39 min, p = .02). Although the in-hospital mortality between the two periods was comparable (5.9% versus 6.7%), 5 of the 7 (71%) COVID-19-positive STEMI patients died. CONCLUSION: The present study revealed a 26% reduction in STEMI admissions and a delay in treatment of STEMI patients. Less exposure to external STEMI triggers (such as ambient air pollution) and/or reluctance to seek medical care are possible explanations of this observation.

Adherence to quality indicators for ST-elevation myocardial infarction and its relation to mortality: a hospital network analysis from the Belgian STEMI database.

AIMS: To assess the adherence to established quality indicators (QIs) for ST-elevation myocardial infarction (STEMI) at the hospital-network level and its relation to outcome. METHODS AND RESULTS: The data of 7774 STEMI patients admitted to 32 STEMI networks during the period 2014-18 were extracted from the Belgian STEMI database. Five QIs [primary percutaneous coronary intervention use, diagnosis-to-balloon time (DiaTB) <90 min, door-to-balloon time (DoTB) <60 min, P2Y12 inhibitor and statin prescription at discharge, and a composite QI score ranging from 0 to 10] were correlated with in-hospital mortality adjusted for differences in baseline risk profile (TIMI risk score). The median composite QI score was 6.5 [interquartile range (IQR) 6-8]. The most important gaps in quality adherence were related to time delays: the recommended DiaTB and DoTB times across the different networks were achieved in 68% (IQR 53-71) and 67% (IQR 50-78), respectively. Quality adherence was better in networks taking care of more high-risk STEMI patients. The median in-hospital mortality among the STEMI networks was 6.4% (IQR 4.1-7.9%). There was a significant independent inverse correlation between the composite QI score and in-hospital mortality (partial correlation coefficient: -0.45, P = 0.013). Stepwise regression analysis revealed that among the individual QIs, prolonged DiaTB was the most important independent outcome predictor. CONCLUSION: Among established STEMI networks, the time delay between diagnosis and treatment was the most variable and the most relevant prognostic QI, underscoring the importance of assessing quality of care throughout the whole network.

Clinical characteristics and outcomes of patients with adult congenital heart disease listed for heart and heart‒lung transplantation in the Eurotransplant region.

BACKGROUND: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation. METHODS: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes. RESULTS: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years. CONCLUSIONS: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list.

A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The BELgium Familial Hypercholesterolaemia STrategy).

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH. This article aims to describe a feasible strategy to facilitate the detection and management of FH among patients hospitalized for CVD. METHODS: A multidisciplinary national panel of lipidologists, cardiologists, endocrinologists and cardio-geneticists developed a three-step diagnostic algorithm, each step including three key aspects of diagnosis, treatment and family care. RESULTS: A sequence of tasks was generated, starting with the process of suspecting FH amongst affected patients admitted for CVD, treating them to LDL-C target, finally culminating in extensive cascade-screening for FH in their family. Conceptually, the pathway is broken down into 3 phases to provide the treating physicians with a time-efficient chain of priorities. CONCLUSIONS: We emphasize the need for optimal collaboration between the various actors, starting with a "vigilant doctor" who actively develops the capability or framework to recognize potential FH patients, continuing with an "FH specialist", and finally involving the patient himself as "FH ambassador" to approach his/her family and facilitate cascade screening and subsequent treatment of relatives.

Do Patients Supported With Continuous-flow Left Ventricular Assist Device Have a Sufficient Risk of Death to Justify a Priority Allocation? A Propensity Score Matched Analysis of Patients Listed in UNOS Status 2.

BACKGROUND: Outcomes of continuous flow left ventricular assist devices (CF-LVADs) as bridge to transplant have significantly improved. The question has arisen whether patients on CF-LVADs have an increased risk of death on the waiting list as to justify a priority allocation (status 1). The aim of this study was to compare the survival after implantation of CF-LVADs with the survival on the waiting list for patients initially listed in United Network for Organ Sharing (UNOS) status 2. METHODS: All patients 18 years or older listed for heart transplantation (HT) in the United States between 2011 and 2013 in UNOS status 2 with no mechanical circulatory support at time of listing were analyzed. Patients were divided into 2 groups, depending on whether they received a new CF-LVAD while listed (CF-LVAD group) or not (NO-LVAD) and were further matched on their propensity score (PS) in a 1:2 ratio. RESULTS: Two hundred eighty-seven CF-LVAD patients were matched to 574 NO-LVAD patients. Survival after CF-LVAD was significantly lower at 24 months compared with waiting list (75.4 ± 4.4% vs 91.2 ± 8.9%, P < 0.0001). Further, survival was not significantly different between the 2 groups at 24 months after transplantation (81.3 ± 5.9% vs 86.7 ± 3.3%, P = 0.3). CONCLUSIONS: Survival of patients listed in UNOS status 2 who receive a CF-LVAD while listed is significantly lower compared to patients who do not receive mechanical support on the waiting list. The current priority in the allocation system given to patients on CF-LVAD seems justified. Further posttransplant survival is not negatively influenced by previous CF-LVAD implantation.

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial.

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30-60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N = 29) or continue their current CNI-based immunosuppression (N = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.

Hypothermic continuous machine perfusion enables preservation of energy charge and functional recovery of heart grafts in an ex vivo model of donation following circulatory death.

OBJECTIVES: Cardiac transplantation using hearts from donors after circulatory death (DCD) is critically limited by the unavoidable warm ischaemia and its related unpredictable graft function. Inasmuch as hypothermic machine perfusion (MP) has been shown to improve heart preservation, we hypothesized that MP could enable the use of DCD hearts for transplantation. METHODS: We recovered 16 pig hearts following anoxia-induced cardiac arrest and cardioplegia. Grafts were randomly assigned to two different groups of 4-h preservation using either static cold storage (CS) or MP (Modified LifePort© System, Organ Recovery Systems©, Itasca, Il). After preservation, the grafts were reperfused ex vivo using the Langendorff method for 60 min. Energetic charge was quantified at baseline, post-preservation and post-reperfusion by measuring lactate and high-energy phosphate levels. Left ventricular contractility parameters were assessed both in vivo prior to ischaemia and ex vivo during reperfusion. RESULTS: Following preservation, the hearts that were preserved using CS exhibited higher lactate levels (57.1 ± 23.7 vs 21.4 ± 12.2 µmol/g; P < 0.001), increased adenosine monophosphate/adenosine triphosphate ratio (0.53 ± 0.25 vs 0.11 ± 0.11; P < 0.001) and lower phosphocreatine/creatine ratio (9.7 ± 5.3 vs 25.2 ± 11; P < 0.001) in comparison with the MP hearts. Coronary flow was similar in both groups during reperfusion (107 ± 9 vs 125 ± 9 ml/100 g/min heart; P = ns). Contractility decreased in the CS group, yet remained well preserved in the MP group. CONCLUSION: MP preservation of DCD hearts results in improved preservation of the energy and improved functional recovery of heart grafts compared with CS.

Hypothermic continuous machine perfusion improves metabolic preservation and functional recovery in heart grafts.

The number of heart transplants is decreasing due to organ shortage, yet the donor pool could be enlarged by improving graft preservation. Hypothermic machine perfusion (MP) has been shown to improve kidney, liver, or lung graft preservation. Sixteen pig hearts were recovered following cardioplegia and randomized to two different groups of 4-hour preservation using either static cold storage (CS) or MP (Modified LifePort© System, Organ Recovery Systems, Itasca, Il). The grafts then underwent reperfusion on a Langendorff for 60 min. Energetic metabolism was quantified at baseline, postpreservation, and postreperfusion by measuring lactate and high-energy phosphates. The contractility index (CI) was assessed both in vivo prior to cardioplegia and during reperfusion. Following reperfusion, the hearts preserved using CS exhibited higher lactate levels (56.63 ± 23.57 vs. 11.25 ± 3.92 µmol/g; P < 0.001), increased adenosine monophosphate/adenosine triphosphate (AMP/ATP) ratio (0.4 ± 0.23 vs. 0.04 ± 0.04; P < 0.001), and lower phosphocreatine/creatine (PCr/Cr) ratio (33.5 ± 12.6 vs. 55.3 ± 5.8; P <0.001). Coronary flow was similar in both groups during reperfusion (107 ± 9 vs. 125 + /-9 ml/100 g/min heart; P = ns). CI decreased in the CS group, yet being well-preserved in the MP group. Compared with CS, MP resulted in improved preservation of the energy state and more successful functional recovery of heart graft.

Giant venous aneurysm jeopardising internal mammary arterial graft patency.

The authors report a 79-year old man with a history of coronary bypass surgery, presenting with acute heart failure and elevated troponin. Coronarography revealed a giant saphenous vein graft aneurysm, which was compressing the left internal mammary artery bypass graft. This was confirmed by a multislice enhanced-ECG gated cardiac CT, showing the venous aneurysm responsible for external compression of the arterial graft and its functional occlusion. Myocardial ischaemia, the mechanism leading to cardiac failure, was confirmed by hypoperfusion of the sub-endocardial area shown by the CT. The aneurysm was surgically removed without complications. The patient recovered and his cardiac function improved. This is the first recorded case of compression of the left internal mammary artery by an giant saphenous vein graft aneurysm having triggered severe myocardial ischaemia and heart failure. The authors review the incidence and complications of giant venous bypass graft aneurysms reported in the literature.

Adult respiratory distress syndrome caused by 2009 H1N1 influenza during pregnancy: success of ECMO for both the mother and the child.

Extracorporeal membrane oxygenation (ECMO) is a technique that provides support to selected patients with severe respiratory failure. During the 2009 H1N1 influenza infection outbreak, ECMO was used with a good impact on survival for pregnant women, who are at higher risk of H1N1 influenza infection. However, there is little information about the survival of fetus post-ECMO therapy in the literature. We present a case report of a pregnant patient with severe adult respiratory distress syndrome secondary to 2009 H1N1 influenza treated with ECMO. The outcome was good both for the mother and her fetus. At 1-year follow-up, her child had no neurological or clinical abnormalities. We conclude that ECMO can be used safely during pregnancy with a good neurological and clinical outcome for the fetus.

Allosensitization in bridge to transplant Novacor left ventricular assist device patients: analysis of long-term outcomes with regard to acute rejection and chronic allograft vasculopathy.

BACKGROUND: The true relevance of allosensitization in patients benefiting from left ventricular assist device (LVAD) as bridge to transplant (BTT) is still debated. Available registry data referred to numerous devices precluding LVAD-specific analysis. Therefore, we studied all patients with Novacor LVAD prior to transplantation. METHODS: From 1985 to 2006, 37 Novacor LVADs were implanted as BTT, with 30 patients surviving to transplantation (81%). Post-LVAD sensitization was determined for anti-HLA-class I and class II IgGs. Study endpoints were overall survival and/or graft loss, > or =3A cellular rejection and chronic allograft vasculopathy (CAV). The results from LVAD patients were compared to non-LVAD primary heart transplant recipients (n=318). RESULTS: After LVAD insertion, 5 out of 27 patients available for analysis developed anti-HLA antibodies (18.5%). The mean anti-HLA titer after Novacor LVAD implantation was 14% [SD 31]. Actuarial 5- and 10-year patient/graft survival for LVAD and non-LVAD transplant recipients were 73% and 55%, and 70% and 55%, respectively (p=NS). Overall prevalence of rejection > or =3A was 23.3 % (LVAD group) and 18.9% (non-LVAD group) (p=NS). At follow-up, the respective incidence of CAV was 8% (LVAD group) and 32.4% (non-LVAD group) (p<0.01). However, mean follow-up was significantly different for LVAD and non-LVAD patients, 46 vs 90 months (p<0.001). CONCLUSION: In this study, allosensitization occurred infrequently after Novacor LVAD implantation. Secondly, analysis of outcome variables shows that Novacor-LVAD BTT patients can anticipate similar survival to non-LVAD patients, thus minimizing the impact of allosensitization after LVAD implantation.

Smart Bag vs. Standard bag in the temporary substitution of the mechanical ventilation.

OBJECTIVE: To compare in intubated patients manually ventilated in order to mirror the ventilator, the respiratory and hemodynamic effects induced by a bag device equipped with an inspiratory gas flow-limiting valve (Smart Bag, 0-Two Medical Technologies Inc., Mississauga, ON, Canada) and a Standard bag. DESIGN: Non-randomized crossover study comparing 13 respiratory and eight hemodynamically paired parameters. Eight intubated patients were manually ventilated, each by three different intensive care workers yielding 24 sets of data for comparison. Data were collected during two sessions of manual ventilation, first with the Standard bag and then with the Smart Bag. Between each session, the patient was reconnected to the ventilator until return to the baseline. Patients, included after coronary surgery, were sedated and paralyzed. SETTING: Intensive Care Unit, university hospital. RESULTS: Compared with Standard bag, the Smart Bag provided a decrease of inspiratory flow (23 +/- 4.7 vs. 47.3 +/- 16.5 l/min) with a decrease of peak pressure (13.3 +/- 2.9 vs. 21.9 +/- 7.3 cmH2O) and tidal volume (9.4 +/- 2.8 vs. 12.4 +/- 2.7 ml/kg). While the expiratory time was similar, the inspiratory time increased (1.83 +/- 0.58 vs. 1.28 +/- 0.46 s) with the Smart Bag, limiting the respiratory rate (14 +/- 5 vs. 17 +/- 6 cycles/min) and the minute volume (8.8 +/- 2.9 vs. 14.4 +/- 4.9 l/min). Finally, it limited the fall of the ETCO2 (27.9 +/- 5.1 vs. 24.3 +/- 5.7 mmHg) and probably the risks of severe respiratory alkalosis. The bags similarly affected hemodynamic states. CONCLUSION: In intubated patients manually ventilated, the Smart Bag limits the risks of excessive airway pressure and the fall of the ETCO2, with hemodynamic effects similar to those of the Standard bag.