Waiting list and Post-Transplant Outcome in Sweden after National Centralization of Heart Transplant Surgery.

BACKGROUND: Previous studies have demonstrated an association between the annual transplantation rate per center and post-operative mortality after heart transplantation. In 2011, Sweden centralized heart transplants and waiting lists, reducing the number of centers from three to two. This study aimed to assess the active waiting time and pre- and post-transplant mortality rates before and after centralization. METHODS: Heart transplantations performed in Sweden between January 1, 2001, and December 31, 2020, were included. Background and donor organ supply data were collected from national registries (Scandiatransplant, STRAX, and SWEDEHEART) and Scandiatransplant, respectively. The Fine and Gray methods were applied to visualize cumulative incidence curves and conduct competing risk regressions. A Cox model was used to adjust for factors influencing time to post-transplant death across eras. RESULTS: When comparing the 10 years before and after centralization, the median active waiting time increased from 54 to 71 days (p=0.015). A decreased risk of mortality on the waiting list was observed in the later era compared to the first (SHR 0.43; [95% CI 0.25-0.74]; p=0.002). The total number of heart transplantation procedures (including pediatric patients) increased by 53% from 377 (mean, 38/year) to 577 (mean, 58/year) in the second era. There was a statistically significant difference in organ utilization between the time eras (p=0.033; Chi2-test). The 30-day and 1-year survival post-transplant rates for adults increased from 90.8% to 97.8% (p<0.001) and from 87.9% to 94.6% (p<0.001), respectively. An adjusted Cox-regression analysis showed a 63% reduction in 1-year mortality between eras (HR 0.37 95%CI 0.22-0.61). CONCLUSIONS: This nationwide retrospective registry study examined patients listed for and undergoing heart transplantation before and after centralization of waiting lists and surgeries in Sweden. Waiting list mortality decreased, and 1-year post-transplantation survival rates improved.

Donor heart dysfunction and graft survival in liver and kidney transplants-A register-based study from Sweden.

BACKGROUND AND AIM: Stress cardiomyopathy in donors can potentially affect graft function and longevity. This study aims to investigate the association between echocardiographic left ventricular ejection fraction (LVEF) < 50%, and/or the presence of left ventricular regional wall motion abnormalities (RWMA) in organ donors, and short- and long-term liver and kidney graft survival. Our secondary aim was to link graft survival with donor and recipient characteristics. METHODS: All donors considered for liver and kidney donation with echocardiographic records at Sahlgrenska University Hospital between 2006 and 2016 were matched with their recipients through the Scandiatransplant register. The studied outcomes were graft survival, re-transplantation, and recipient death. Kaplan-Meier curves were used to plot time to event. Multivariate Cox-regression was used to test independence. RESULTS: There were 370 liver donors and 312 kidney donors (matched with 458 recipients) with echocardiographic records at Sahlgrenska University Hospital between June 2006 and November 2016. Of patients with LV dysfunction by echocardiography, there were 102 liver- and 72 kidney donors. Univariate survival analyses showed no statistical difference in the short- and long-term graft survival from donors with LV dysfunction compared to donors without. Donor age > 65 years, recipient re-transplantation and recipient liver tumor were predictors of worse outcome in liver transplants (p < .05). Donor age > 65, donor hypertension, recipient re-transplantation, and a recipient diagnosis of diabetes or nephritis/glomerulonephritis had a negative association with graft survival in kidney transplants (p < .05). CONCLUSION: We found no significant association between donor LV dysfunction and short- and long-term graft survival in liver and kidney transplants, suggesting that livers and kidneys from such donors can be safely transplanted.

Severe heart failure in a unique case of cobalamin-C-deficiency resolved with LVAD implantation and subsequent heart transplantation.

Introduction Cobalamin c deficiency (cblC), an inborn error of vitamin B12 metabolism, is caused by mutations of the MMACHC gene. It usually leads to a multisystemic disease; 50% of all patients with cblC have various structural heart defects. Severe congestive heart failure (HF) may also occur and its prognosis is poorly documented. Case report We present the case of a young man who had been diagnosed with cblC due to C331T mutation in the MMACHC gene at the age of 3 days and had been treated with substitution therapy (OH-Cbl, mecobalamine, carnitine, betaine, and calcium folinate) since then. He had mildly impaired cognitive function; an ectopic hypophysis/pituitary insufficiency, with adequate hormone replacement therapy; obstructive sleep apnea syndrome, treated with CPAP, bronchial asthma, and obesity (BMI of 30). The liver and kidney functions were normal. He developed severe dilated cardiomyopathy and HF at the age of 12y. With medical treatment, his condition improved and he was stable (NYHA class II) for several years. Six years later, his status deteriorated rapidly, as he developed advanced HF, INTERMACS 3. The cardiac ultrasound revealed dilated ventricles with severely depressed ejection fraction (EF), increased filling pressures, and pulmonary hypertension (sPAP 60 mmHg). Cardiac MRI showed extremely dilated chambers (LVedv 609 mL, RVedv 398 mL) with pronounced non-compaction, and a left ventricle EF of 13%. A primary prophylactic ICD and a left ventricular assist device (LVAD/HM3) were implanted, and the patient was subsequently listed for heart transplantation (HTx). After 25 months on the waiting list, he underwent an uncomplicated HTx. However postoperatively, he got two episodes of cardiac tamponade, as well as mediastinitis, treated with antibiotics and vaccum assisted closure. He developed severe kidney failure, which fully recovered after two months, and was treated successfully for an early moderate allograft rejection (ISHT 2). At the latest outward visit, twelve months after HTx, the patient was doing excellent. Summary To the best of our knowledge, this is the first ever reported case of a patient with CblC undergoing an LVAD implantation and subsequently a HTx. Although both interventions were complicated with bleeding events, this seems to be a treatment option for advanced HF in patients with CblC.

Management of infectious disease syndromes in thoracic organ transplants and mechanical circulatory device recipients: a Delphi panel.

PURPOSE: Antimicrobial misuse contributes to antimicrobial resistance in thoracic transplant (TTx) and mechanical circulatory support (MCS) recipients. This study uses a modified Delphi method to define the expected appropriate antimicrobial prescribing for the common clinical scenarios encountered in TTx and MCS recipients. METHODS: An online questionnaire on managing 10 common infectious disease syndromes was submitted to a multidisciplinary Delphi panel of 25 experts from various disciplines. Consensus was predefined as 80% agreement for each question. Questions where consensus was not achieved were discussed during live virtual live sessions adapted by an independent process expert. RESULTS: An online survey of 62 questions related to 10 infectious disease syndromes was submitted to the Delphi panel. In the first round of the online questionnaire, consensus on antimicrobial management was reached by 6.5% (4/62). In Round 2 online live discussion, the remaining 58 questions were discussed among the Delphi Panel members using a virtual meeting platform. Consensus was reached among 62% (36/58) of questions. Agreement was not reached regarding the antimicrobial management of the following six clinical syndromes: (1) Burkholderia cepacia pneumonia (duration of therapy); (2) Mycobacterium abscessus (intra-operative antimicrobials); (3) invasive aspergillosis (treatment of culture-negative but positive BAL galactomannan) (duration of therapy); (4) respiratory syncytial virus (duration of antiviral therapy); (5) left ventricular assist device deep infection (initial empirical antimicrobial coverage) and (6) CMV (duration of secondary prophylaxis). CONCLUSION: This Delphi panel developed consensus-based recommendations for 10 infectious clinical syndromes seen in TTx and MCS recipients.

Cardiopulmonary bypass management and acute kidney injury in cardiac surgery patients.

BACKGROUND: Cardiopulmonary bypass (CPB) ensures tissue oxygenation during cardiac surgery. New technology allows continuous registration of CPB variables during the operation. The aim of the present investigation was to study the association between CPB management and the risk of postoperative acute kidney injury (AKI). METHODS: This observational study based on prospectively registered data included 2661 coronary artery bypass grafting and/or valve patients operated during 2016-2020. Individual patient characteristics and postoperative outcomes collected from the SWEDEHEART registry were merged with CPB variables automatically registered every 20 s during CPB. Associations between CPB variables and AKI were analyzed with multivariable logistic regression models adjusted for patient characteristics. RESULTS: In total, 387 patients (14.5%) developed postoperative AKI. After adjustments, longer time on CPB and aortic cross-clamp, periods of compromised blood flow during aortic cross-clamp time, and lower nadir hematocrit were associated with the risk of AKI, while mean blood flow, bladder temperature, central venous pressure, and mixed venous oxygen saturation were not. Patient characteristics independently associated with AKI were advanced age, higher body mass index, hypertension, diabetes mellitus, atrial fibrillation, lower left ventricular ejection fraction, estimated glomerular filtration rate <60 or >90 mL/min/m2 , and preoperative hemoglobin concentration below or above the normal sex-specific range. CONCLUSIONS: To reduce the risk of AKI after cardiac surgery, aortic clamp time and CPB time should be kept short, and low hematocrit and periods of compromised blood flow during aortic cross-clamp time should be avoided if possible.

Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial.

BACKGROUND: Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation. METHODS: ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18-70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2-3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05-0·1 mg/kg before transplantation and 0·1-0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27). FINDINGS: Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31-48]) in the ciclosporin group and 16 patients (13% [8-21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15-0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65-81] for ciclosporin vs 79% [70-85] for tacrolimus; HR 0·72 [95% CI 0·41-1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26-0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event. INTERPRETATION: Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation. FUNDING: Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark.

Non-ischaemic preservation of the donor heart in heart transplantation: protocol design and rationale for a randomised, controlled, multicentre clinical trial across eight European countries.

INTRODUCTION: Ischaemic cold static storage (ICSS) is the gold standard in donor heart preservation. This ischaemic time frame renders a time constraint and risk for primary graft dysfunction. Cold oxygenated heart perfusion, known as non-ischaemic heart preservation (NIHP), theoretically limits the ischaemic time, while holding on to the known advantage of hypothermia and cardioplegia, a low metabolic rate. METHODS AND ANALYSIS: The NIHP 2019 study is an international, randomised, controlled, open, multicentre clinical trial in 15 heart transplantation centres in 8 European countries and includes 202 patients undergoing heart transplantation, allocated 1:1 to NIHP or ICSS. Enrolment is estimated to be 30 months after study initiation. The patients are followed for 12 months after transplantation.The primary objective is to evaluate the effect of NIHP on survival, allograft function and rejection episodes within the first 30 days after transplantation. The secondary objectives are to compare treatment groups with respect to survival, allograft function, cardiac biomarkers, rejection episodes, allograft vasculopathy, adverse events and adverse device effects within 12 months. ETHICS AND DISSEMINATION: This protocol was approved by the Ethics Committee (EC) for Research UZ/KU Leuven, Belgium, the coordinating EC in Germany (Bei Der LMU München), the coordinating EC in the UK (West Midlands-South Birmingham Research), the EC of Hospital Puerta de Hierro, Madrid, Spain, the EC of Göteborg, Sweden, the coordinating EC in France, the EC of Padova, Italy and the EC of the University of Vienna, Austria. This study will be conducted in accordance with current local regulations and international applicable regulatory requirements according to the principles of the Declaration of Helsinki and ISO14155:2020. Main primary and secondary outcomes will be published on modified intention-to-treat population and per-protocol population. TRIAL REGISTRATION NUMBER: NCT03991923.

["Samurai cannulation" less time-consuming than other techniques for treating iatrogenic type A aortic dissection]. / Samurajkanylering ­ snabb och säker vid iatrogen aortadissektion.

Iatrogenic type A aortic dissection is a life-threatening condition associated with high morbidity and mortality. Traditionally, cannulation of the femoral artery or axillary artery has been preferred for arterial access, but in 2007 a new technique including direct cannulation of the ascending aorta was presented. The technique is known as "samurai cannulation" because of the quick incision of the aorta. It has been shown to be less time-consuming than other techniques, which is favorable in acute situations in patients with hemodynamic instability.

Absolute Quantification of Donor-Derived Cell-Free DNA in Pediatric and Adult Patients After Heart Transplantation: A Prospective Study.

In this prospective study we investigated a cohort after heart transplantation with a novel PCR-based approach with focus on treated rejection. Blood samples were collected coincidentally to biopsies, and both absolute levels of dd-cfDNA and donor fraction were reported using digital PCR. 52 patients (11 children and 41 adults) were enrolled (NCT03477383, clinicaltrials.gov), and 557 plasma samples were analyzed. 13 treated rejection episodes >14 days after transplantation were observed in 7 patients. Donor fraction showed a median of 0.08% in the cohort and was significantly elevated during rejection (median 0.19%, p < 0.0001), using a cut-off of 0.1%, the sensitivity/specificity were 92%/56% (AUC ROC-curve: 0.78). Absolute levels of dd-cfDNA showed a median of 8.8 copies/mL and were significantly elevated during rejection (median 23, p = 0.0001). Using a cut-off of 7.5 copies/mL, the sensitivity/specificity were 92%/43% for donor fraction (AUC ROC-curve: 0.75). The results support the feasibility of this approach in analyzing dd-cfDNA after heart transplantation. The obtained values are well aligned with results from other trials. The possibility to quantify absolute levels adds important value to the differentiation between ongoing graft damage and quiescent situations.

Design and Rationale of Cytokine Filtration in Lung Transplantation (GLUSorb): Protocol for a Multicenter Clinical Randomized Controlled Trial.

BACKGROUND: Lung transplantation (LTx) is the only treatment option for end-stage lung disease. Despite improvements, primary graft dysfunction (PGD) remains the leading cause of early mortality and precipitates chronic lung allograft dysfunction, the main factor in late mortality after LTx. PGD develops within the first 72 hours and impairs the oxygenation capacity of the lung, measured as partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2). Increasing the PaO2/FiO2 ratio is thus critical and has an impact on survival. There is a general lack of effective treatments for PGD. When a transplanted lung is not accepted by the immune system in the recipient, a systemic inflammatory response starts where cytokines play a critical role in initiating, amplifying, and maintaining the inflammation leading to PGD. Cytokine filtration can remove these cytokines from the circulation, thus reducing inflammation. In a proof-of-concept preclinical porcine model of LTx, cytokine filtration improved oxygenation and decreased PGD. In a feasibility study, we successfully treated patients undergoing LTx with cytokine filtration (ClinicalTrials.gov; NCT05242289). OBJECTIVE: The purpose of this clinical trial is to demonstrate the superiority of cytokine filtration in improving LTx outcome, based on its effects on oxygenation ratio, plasma levels of inflammatory markers, PGD incidence and severity, lung function, kidney function, survival, and quality of life compared with standard treatment with no cytokine filtration. METHODS: This study is a Swedish national interventional randomized controlled trial involving 116 patients. Its primary objective is to investigate the potential benefits of cytokine filtration when used in conjunction with LTx. Specifically, this study aims to determine whether the application of cytokine filtration, administered for a duration of 12 hours within the initial 24 hours following a LTx procedure, can lead to improved patient outcomes. This study seeks to assess various aspects of patient recovery and overall health to ascertain the potential positive impact of this intervention on the posttransplantation course. RESULTS: The process of patient recruitment for this study is scheduled to commence subsequent to a site initiation visit, which was slated to take place on August 28, 2023. The primary outcome measure that will be assessed in this research endeavor is the oxygenation ratio, a metric denoted as the highest PaO2/FiO2 ratio achieved by patients within a 72-hour timeframe following their LTx procedure. CONCLUSIONS: We propose that cytokine filtration could enhance the overall outcomes of LTx. Our hypothesis suggests potential improvements in LTx outcome and patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05526950; https://www.clinicaltrials.gov/study/NCT05526950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/52553.

Regional transcriptomic profiling reveals immune system enrichment in nonfailing atria and all chambers of the failing human heart.

The different chambers of the human heart demonstrate regional physiological traits and may be differentially affected during pathological remodeling, resulting in heart failure. Few previous studies, however, have characterized the different chambers at a transcriptomic level. We, therefore, conducted whole tissue RNA sequencing and gene set enrichment analysis of biopsies collected from the four chambers of adult failing (n = 8) and nonfailing (n = 11) human hearts. Atria and ventricles demonstrated distinct transcriptional patterns. When compared with nonfailing ventricles, the transcriptional pattern of nonfailing atria was enriched for many gene sets associated with cardiogenesis, the immune system and bone morphogenetic protein (BMP), transforming growth factor-ß (TGF-ß), MAPK/JNK, and Wnt signaling. Differences between failing and nonfailing hearts were also determined. The transcriptional pattern of failing atria was distinct compared with that of nonfailing atria and enriched for gene sets associated with the innate and adaptive immune system, TGF-ß/SMAD signaling, and changes in endothelial, smooth muscle cell, and cardiomyocyte physiology. Failing ventricles were also enriched for gene sets associated with the immune system. Based on the transcriptomic patterns, upstream regulators associated with heart failure were identified. These included many immune response factors predicted to be similarly activated for all chambers of failing hearts. In summary, the heart chambers demonstrate distinct transcriptional patterns that differ between failing and nonfailing hearts. Immune system signaling may be a hallmark of all four heart chambers in failing hearts and could constitute a novel therapeutic target.NEW & NOTEWORTHY The transcriptomic patterns of the four heart chambers were characterized in failing and nonfailing human hearts. Both nonfailing atria had distinct transcriptomic patterns characterized by cardiogenesis, the immune system and BMP/TGF-ß, MAPK/JNK, and Wnt signaling. Failing atria and ventricles were enriched for gene sets associated with the innate and adaptive immune system. Key upstream regulators associated with heart failure were identified, including activated immune response elements, which may constitute novel therapeutic targets.

Anti-Ro52 positivity is associated with progressive interstitial lung disease in systemic sclerosis-an exploratory study.

BACKGROUND: Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Prognostic biomarkers are needed to identify SSc-ILD patients at risk for progressive pulmonary fibrosis. This study investigates autoantibodies measured in bronchoalveolar lavage (BAL) fluid and in serum in reference to the clinical disease course of SSc-ILD. METHODS: Fifteen patients with new onset SSc-ILD underwent bronchoscopy. Autoantibody levels were analyzed using addressable laser bead immunoassay from BAL fluid and the serum. In a separate longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years. Linear mixed effect models were created to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry. RESULTS: Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc. CONCLUSIONS: This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical and immunohistochemical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD.

Heart transplantation in patients bridged with mechanical circulatory support: outcome comparison with matched controls.

AIMS: Due to the shortage of heart donors, increasing numbers of heart transplantation (HTx) candidates are receiving long-term mechanical circulatory support (MCS) as bridge-to-transplantation. Treatment with MCS is associated with increased formation of anti-human leukocyte antigen antibodies (allosensitization), but whether this affects post-HTx outcomes is unclear. METHODS AND RESULTS: We included all adult patients who received long-term MCS as bridge-to-transplantation and underwent subsequent HTx at our centre between 2008 and 2018. We also enrolled medically treated HTx recipients without prior MCS as controls. These controls were matched by age, sex, diagnosis, and transplantation era. Outcome parameters were compared between the two study groups. A total of 126 patients (48 ± 15 years, 84% male) were included of whom 64 were bridged with MCS and 62 were matched controls. Pre-HTx allosensitization occurred more frequently in the MCS group than in the control group (27% vs. 11%, P = 0.03). At post-HTx year 10, the overall survival probability was 84% among patients treated with MCS and 90% among those medically managed (P = 0.32). At post-HTx year 1, freedom from treated rejections (≥ISHLT 2R) was 69% in the MCS group and 70% in the control group (P = 0.94); and freedom from any rejection was 8% and 5%, respectively (P = 0.98). There were no differences in renal function or cardiac allograft vasculopathy (grade ≥ 1) between groups at 1, 3, and 5 years post-HTx. CONCLUSIONS: Although patients treated with MCS had a higher frequency of pre-HTx allosensitization, there were no significant differences in post-HTx graft survival, biopsy-proven rejections, or renal function as compared with patients not bridged with MCS.

Metagenomic sequencing of human cardiac tissue reveals Microbial RNA which correlates with Toll-like receptor-associated inflammation in patients with heart disease.

Cardiovascular disease (CVD) is strongly associated with chronic low-grade inflammation, involving activated Toll-like receptors and their downstream cellular machinery. Moreover, CVD and other related inflammatory conditions are associated with infiltration of bacteria and viruses originating from distant body sites. Thus, in this study we aimed to map the presence of microbes in the myocardium of patients with heart disease that we previously found to display upregulated Toll-like receptor signaling. We performed metagenomics analysis of atrial cardiac tissue from patients undergoing coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) and compared with atrial cardiac tissue from organ donors. A total of 119 species of bacteria and seven species of virus were detected in the cardiac tissue. RNA expression of five bacterial species were increased in the patient group of which L. kefiranofaciens correlated positively with cardiac Toll-like receptor-associated inflammation. Interaction network analysis revealed four main gene set clusters involving cell growth and proliferation, Notch signaling, G protein signaling and cell communication in association with L. kefiranofaciens RNA expression. Taken together, intracardial expression of L. kefiranofaciens RNA correlates with pro-inflammatory markers in the diseased cardiac atrium and may have an effect on specific signaling processes important for cell growth, proliferation and cell communication.

Alveolar epithelial cells are competent producers of interstitial extracellular matrix with disease relevant plasticity in a human in vitro 3D model.

Alveolar epithelial cells (AEC) have been implicated in pathological remodelling. We examined the capacity of AEC to produce extracellular matrix (ECM) and thereby directly contribute towards remodelling in chronic lung diseases. Cryopreserved type 2 AEC (AEC2) from healthy lungs and chronic obstructive pulmonary disease (COPD) afflicted lungs were cultured in decellularized healthy human lung slices for 13 days. Healthy-derived AEC2 were treated with transforming growth factor ß1 (TGF-ß1) to evaluate the plasticity of their ECM production. Evaluation of phenotypic markers and expression of matrisome genes and proteins were evaluated by RNA-sequencing, mass spectrometry and immunohistochemistry. The AEC2 displayed an AEC marker profile similar to freshly isolated AEC2 throughout the 13-day culture period. COPD-derived AECs proliferated as healthy AECs with few differences in gene and protein expression while retaining increased expression of disease marker HLA-A. The AEC2 expressed basement membrane components and a complex set of interstitial ECM proteins. TGF-ß1 stimuli induced a significant change in interstitial ECM production from AEC2 without loss of specific AEC marker expression. This study reveals a previously unexplored potential of AEC to directly contribute to ECM turnover by producing interstitial ECM proteins, motivating a re-evaluation of the role of AEC2 in pathological lung remodelling.

Pulmonary 5-HT2B receptor expression in fibrotic interstitial lung diseases.

Pulmonary fibrosis is a severe condition in interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-ILD, where the underlying mechanism is not well defined and with no curative treatments available. Serotonin (5-HT) signaling via the 5-HT2B receptor has been recognized as a promising preclinical target for fibrosis. Despite this, the involvement of the 5-HT2B receptor in fibrotic ILD is widely unexplored. This work highlights the spatial pulmonary distribution of the 5-HT2B receptor in patients with IPF and systemic sclerosis-ILD. We show that the 5-HT2B receptor is located in typical pathological structures e.g. honeycomb cysts and weakly in fibroblast foci. Together with immunohistochemistry and immunofluorescence stainings of patient derived distal lung tissues, we identified cell targets for 5-HT2B receptor interference in type II alveolar epithelial cells, endothelial cells and M2 macrophages. Our results emphasize the role of 5-HT2B receptor as a target in lung fibrosis, warranting further consideration in targeting fibrotic ILDs.

Atrial natriuretic peptide in the prevention of acute renal dysfunction after heart transplantation-a randomized placebo-controlled double-blind trial.

BACKGROUND: Acute kidney injury (AKI) and renal dysfunction after heart transplantation are common and serious complications. Atrial natriuretic peptide (ANP) has been shown to increase glomerular filtration rate (GFR) and exert renoprotective effects when used for the prevention/treatment of AKI in cardiac surgery. We tested the hypothesis that intraoperative and postoperative administration of ANP could prevent a postoperative decrease in renal function early after heart transplantation. METHODS: Seventy patients were randomized to receive either ANP (50 ng/kg/min) (n = 33) or placebo (n = 37) starting after induction of anesthesia and continued for 4 days after heart transplantation or until treatment with dialysis was started. The primary end-point of the present study was measured GFR (mGFR) at day 4, assessed by plasma clearance of a renal filtration marker. Also, the incidence of postoperative AKI and dialysis were assessed. RESULTS: Median (IQR) mGFR at day 4 postoperatively was 60.0 (57.0) and 50.1 (36.3) ml/min/1.72 m2 for the placebo and ANP groups, respectively (p = .705). During ongoing ANP infusion, the need for dialysis was 21.6% and 9.1% for the placebo and ANP groups, respectively (p = .197). The incidences of AKI for the placebo and the ANP groups were 76.5% and 63.6%, respectively (p = .616). The incidences of AKI stage 1 were 32.4% and 21.2% for the placebo and ANP groups, respectively (p = .420) and for AKI stage 2 or 3, 37.8% and 42.4%, respectively (p = .808). CONCLUSION: The study failed to detect that ANP infusion attenuates renal dysfunction or decreases the incidence of AKI after heart transplantation.

Hemostatic effects of a dextran-based priming solution for cardiopulmonary bypass: A secondary analysis of a randomized clinical trial.

INTRODUCTION: Intravascular fluids administered to patients may influence hemostasis. In patients undergoing cardiac surgery with cardiopulmonary bypass, the heart-lung machine is primed with 1300 ml of fluid. We assessed postoperative coagulation and platelet function in patients randomized to two different priming solutions, one colloid-based (dextran 40) and one crystalloid-based. MATERIALS AND METHODS: Eighty-four elective cardiac surgery patients were randomized to either a dextran-based prime or Ringer's acetate with added mannitol. Blood samples were collected before, and 2 and 24 h after cardiopulmonary bypass. Coagulation was assessed by standard coagulation tests and rotational thromboelastometry. Platelet function was assessed with impedance aggregometry. Bleeding volumes and transfusion requirements were recorded. RESULTS: Comparing the groups 2 h after bypass, the dextran group showed lower hemoglobin concentration, hematocrit, platelet count, and fibrinogen concentration, and higher INR and aPTT, as well as longer clot formation time (+41 ± 21 % vs. +8 ± 18 %, p < 0.001) and a larger reduction in fibrinogen-dependent clot strength (-37 ± 12 % vs. -7 ± 20 %, p < 0.001). Adenosine diphosphate-dependent platelet activation was reduced in the dextran group but not in the crystalloid group 2 h after bypass (-14 ± 29 % vs. -1 ± 41 %, p = 0.041). No significant between-group differences in hemostatic variables remained after 24 h, and no significant differences in perioperative bleeding volumes, re-explorations for bleeding, or transfusion rates were observed. CONCLUSIONS: Compared to a crystalloid solution, a dextran-based prime had measurable negative impact on hemostatic variables but no detectable increase in bleeding volume or transfusion requirements in cardiac surgery patients.

Subtyping of cardiac amyloidosis by mass spectrometry-based proteomics of endomyocardial biopsies.

BACKGROUND: Cardiac amyloidosis is a severe condition leading to restrictive cardiomyopathy and heart failure. Mass spectrometry-based methods for cardiac amyloid subtyping have become important diagnostic tools but are currently used only in a few reference laboratories. Such methods include laser-capture microdissection to ensure the specific analysis of amyloid deposits. Here we introduce a direct proteomics-based method for subtyping of cardiac amyloidosis. METHODS: Endomyocardial biopsies were retrospectively analysed from fresh frozen material of 78 patients with cardiac amyloidosis and from 12 biopsies of unused donor heart explants. Cryostat sections were digested with trypsin and analysed with liquid chromatography - mass spectrometry, and data were evaluated by proteomic software. RESULTS: With a diagnostic threshold set to 70% for each of the four most common amyloid proteins affecting the heart (LC κ, LC λ, TTR and SAA), 65 of the cases (87%) could be diagnosed, and of these, 61 cases (94%) were in concordance with the original diagnoses. The specimens were also analysed for the summed intensities of the amyloid signature proteins (ApoE, ApoA-IV and SAP). The intensities were significantly higher (p < 0.001) for all assigned cases compared with controls. CONCLUSION: Cardiac amyloidosis can be successfully subtyped without the prior enrichment of amyloid deposits with laser microdissection.

[Cardiac transplantation and donation in Icelandic patients - indications and outcome].

INTRODUCTION: Information on the number, indications and outcome of cardiac transplantations in Icelandic patients is scarce, as is information on the number of hearts donated from Iceland for cardiac transplantation. MATERIAL AND METHODS: A retrospective study on patients receiving heart transplantation from the first procedure in 1988 until March 2019. Clinical information was gathered from Landspitali Transplantation Clinic, patient charts, and information on donated hearts from the Icelandic Donation Registry. Age-standardized incidence of the procedure was calculated, and overall survival (Kaplan-Meier) estimated. Mean follow-up was 10.3 years. RESULTS: Altogether 24 patients (19 males, median age 38 years, range: 4-65 years) underwent cardiac transplantation; that included one re-transplantation, three simultaneous heart- and lung transplants and two heart- and kidney transplants. The transplantations were performed in Gothenburg (n=20), London (n=3) and Copenhagen (n=2). Most common indications were dilated cardiomyopathy (n=10), congenital heart disease (n=4), and viral myocarditis (n=3). Five patients were bridged left ventricular-assist device preoperatively. Overall survival at 1 and 5 years was 91% and 86%, respectively; median survival being 24 years. The incidence of cardiac transplantation was 2.7 heart-TX pmp/year but increased to 4.6 heart-TX pmp/year after 2008 (p=0.01). During the same period 42 hearts were donated from Iceland for transplantation abroad, the first in 2002 and increasing from 0.8 to 3.0 hearts/year during the first and second half of the study-period, respectively. CONCLUSION: Survival of Icelandic cardiac transplant recipients is good and comparable to larger transplant centers overseas. Number of hearts donated from Iceland have increased and currently Iceland donates twice as many hearts at it receives.