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

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

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.

Donor Fractions of Cell-Free DNA Are Elevated During CLAD But Not During Infectious Complications After Lung Transplantation.

During the last few years, cell-free DNA (cfDNA) has emerged as a possible non-invasive biomarker for prediction of complications after lung transplantation. We previously published a proof-of-concept study using a digital droplet polymerase chain reaction (ddPCR)-based method for detection of cfDNA. In the current study, we aimed to further evaluate the potential clinical usefulness of detecting chronic lung allograft dysfunction (CLAD) using three different ddPCR applications measuring and calculating the donor fraction (DF) of cfDNA as well as one method using the absolute amount of donor-derived cfDNA. We analyzed 246 serum samples collected from 26 lung transplant recipients. Nine of the patients had ongoing CLAD at some point during follow-up. All four methods showed statistically significant elevation of the measured variable in the CLAD samples compared to the non-CLAD samples. The results support the use of ddPCR-detected cfDNA as a potential biomarker for prediction of CLAD. These findings need to be validated in a subsequent prospective study.

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.

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.

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.

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.

Dextran-based priming solution during cardiopulmonary bypass attenuates renal tubular injury-A secondary analysis of randomized controlled trial in adult cardiac surgery patients.

BACKGROUND: Acute kidney injury (AKI) is a well-known complication after cardiac surgery and cardiopulmonary bypass (CPB). In the present secondary analysis of a blinded randomized controlled trial, we evaluated the effects of a colloid-based versus a conventional crystalloid-based prime on tubular injury and postoperative renal function in patients undergoing cardiac surgery with CPB. METHODS: Eighty-four adult patients undergoing cardiac surgery with CPB were randomized to receive either a crystalloid- or colloid- (dextran 40) based CPB priming solution. The crystalloid solution was based on Ringer-Acetate plus mannitol. The tubular injury biomarker, N-acetyl-b-D-glucosaminidase (NAG), serum creatinine and diuresis were measured before, during and after CPB. The incidence of AKI was assessed according to the KDIGO criteria. RESULTS: The urinary-NAG/urinary-creatinine ratio rose in both groups during and after CPB, with a more pronounced increase in the crystalloid group (p = .038). One hour after CPB, the urinary-NAG/urinary-creatinine ratio was 88% higher in the crystalloid group (4.7 ± 6.3 vs. 2.5 ± 2.7, p = .045). Patients that received the dextran 40-based priming solution had a significantly lower intraoperative diuresis (p < .001) compared to the crystalloid group. The incidence of AKI was 18% in the colloid and 22% in the crystalloid group (p = .66). Postoperative serum creatinine did not differ between groups. CONCLUSIONS: In patients undergoing cardiac surgery with CPB, colloid-based priming solution (dextran 40) induced less renal tubular injury compared to a crystalloid-based priming solution. Whether a colloid-based priming solution will improve renal outcome in high-risk cardiac surgery, or not, needs to be evaluated in future studies on higher risk cardiac surgery patients.

Serum biomarkers of brain injury after uncomplicated cardiac surgery: Secondary analysis from a randomized trial.

BACKGROUND: Postoperative cognitive dysfunction is common after cardiac surgery. Postoperative measurements of brain injury biomarkers may identify brain damage and predict cognitive dysfunction. We describe the release patterns of five brain injury markers in serum and plasma after uncomplicated cardiac surgery. METHODS: Sixty-one elective cardiac surgery patients were randomized to undergo surgery with either a dextran-based prime or a crystalloid prime. Blood samples were taken immediately before surgery, and 2 and 24 h after surgery. Concentrations of the brain injury biomarkers S100B, glial fibrillary acidic protein (GFAP), tau, neurofilament light (NfL) and neuron-specific enolase (NSE)) and the blood-brain barrier injury marker ß-trace protein were analyzed. Concentrations of brain injury biomarkers were correlated to patients' age, operation time, and degree of hemolysis. RESULTS: No significant difference in brain injury biomarkers was observed between the prime groups. All brain injury biomarkers increased significantly after surgery (tau +456% (25th-75th percentile 327%-702%), NfL +57% (28%-87%), S100B +1145% (783%-2158%), GFAP +17% (-3%-43%), NSE +168% (106%-228%), while ß-trace protein was reduced (-11% (-17-3%). Tau, S100B, and NSE peaked at 2h, NfL and GFAP at 24 h. Postoperative concentrations of brain injury markers correlated to age, operation time, and/or hemolysis. CONCLUSION: Uncomplicated cardiac surgery with cardiopulmonary bypass is associated with an increase in serum/plasma levels of all the studied injury markers, without signs of blood-brain barrier injury. The biomarkers differ markedly in their levels of release and time course. Further investigations are required to study associations between perioperative release of biomarkers, postoperative cognitive function and clinical outcome.

A novel echocardiographic right ventricular dysfunction score can identify hemodynamic severity profiles in left ventricular dysfunction.

PURPOSE: Recognition of congestion and hypoperfusion in patients with chronic left ventricular dysfunction (LVD) has therapeutic and prognostic implications. In the present study we hypothesized that a multiparameter echocardiographic grading of right ventricular dysfunction (RVD) can facilitate the characterization of hemodynamic profiles. METHODS: Consecutive patients (n = 105, age 53 ± 14 years, males 77%, LV ejection fraction 28 ± 11%) referred for heart transplant or heart failure work-up, with catheterization and echocardiography within 48 h, were reviewed retrospectively. Three hemodynamic profiles were defined: compensated LVD (cLVD, normal pulmonary capillary wedge pressure (PCWP < 15 mmHg) and normal mixed venous saturation (SvO2 ≥ 60%)); decompensated LVD (dLVD, with increased PCWP) and LV failure (LVF, increased PCWP and reduced SvO2). We established a 5-point RVD score including pulmonary hypertension, reduced tricuspid annular plane systolic excursion, RV dilatation, ≥ moderate tricuspid regurgitation and increased right atrial pressure. RESULTS: The RVD score [median (IQR 25%;75%)] showed significant in-between the three groups differences with 1 (0;1), 1 (0.5;2) and 3.0 (2;3.5) in patients with cLVD, dLVD and LVF, respectively. The finding of RVD score ≥ 2 or ≥ 4 increased the likelihood of decompensation or LVF 5.2-fold and 6.7-fold, respectively. On the contrary, RVD score < 1 and < 2 reduced the likelihood 11.1-fold and 25-fold, respectively. The RVD score was more helpful than standard echocardiography regarding identification of hemodynamic profiles. CONCLUSIONS: In this proof of concept study an echocardiographic RVD score identified different hemodynamic severity profiles in patients with chronic LVD and reduced ejection fraction. Further studies are needed to validate its general applicability.

Whole Blood Adsorber During CPB and Need for Vasoactive Treatment After Valve Surgery in Acute Endocarditis: A Randomized Controlled Study.

OBJECTIVES: Patients with endocarditis requiring urgent valvular surgery with cardiopulmonary bypass are at a high risk of developing systemic inflammatory response syndrome and septic shock, necessitating intensive use of vasopressors after surgery. The use of a cytokine hemoadsorber (CytoSorb, CytoSorbents Europe GmbH, Germany) during cardiac surgery has been suggested to reduce the risk of inflammatory activation. The study authors hypothesized that adding a cytokine adsorber would reduce cytokine burden, which would translate into improved hemodynamic stability. DESIGN: A randomized, controlled, nonblinded clinical trial. SETTING: At a university hospital, tertiary referral center. PARTICIPANTS: Nineteen patients with endocarditis undergoing valve surgery. INTERVENTION: A cytokine hemoadsorber integrated into the cardiopulmonary bypass circuit. MEASUREMENTS AND MAIN RESULTS: The accumulated norepinephrine dose in the intervention group was half or less at all postoperative time points compared to the control group, although it did not reach statistical significance; at 24 and 48 hours (median 36 [25-75 percentiles; 12-57] µg v 114 [25-559] µg, p = 0.11 and 36 [12-99] µg v 261 [25-689] µg, p = 0.09). There was no significant difference in chest tube output, but there was a significantly lower need for the transfusion of red blood cells (285 [0-657] mL v 1,940 [883-2,148] mL, p = 0.03). CONCLUSIONS: There was no statistically significant difference between the groups with regard to vasopressor use after surgery for endocarditis with the use of a cytokine hemoadsorber during cardiopulmonary bypass. Additional, larger randomized controlled trials are needed to definitely assess the potential effect.

[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.

Impaired Differentiation of Chronic Obstructive Pulmonary Disease Bronchial Epithelial Cells Grown on Bronchial Scaffolds.

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation, small airway remodeling, and emphysema. Airway remodeling in patients with COPD involves both the airway epithelium and the subepithelial extracellular matrix (ECM). However, it is currently unknown how epithelial remodeling in COPD airways depends on the relative influence from inherent defects in the epithelial cells and alterations in the ECM. To address this, we analyzed global gene expression in COPD human bronchial epithelial cells (HBEC) and normal HBEC after repopulation on decellularized bronchial scaffolds derived from patients with COPD or donors without COPD. COPD HBEC grown on bronchial scaffolds showed an impaired ability to initiate ciliated-cell differentiation, which was evident on all scaffolds regardless of their origin. In addition, although normal HBEC were less affected by the disease state of the bronchial scaffolds, COPD HBEC showed a gene expression pattern indicating increased proliferation and a retained basal-cell phenotype when grown on COPD bronchial scaffolds compared with normal bronchial scaffolds. By using mass spectrometry, we identified 13 matrisome proteins as being differentially abundant between COPD bronchial scaffolds and normal bronchial scaffolds. These observations are consistent with COPD pathology and suggest that both epithelial cells and the ECM contribute to epithelial-cell remodeling in COPD airways.

COVID-19 in lung transplant recipients: an overview of the Swedish national experience.

Although it is known that solid organ transplant recipients fare worse after COVID-19 infection, data on the impact of COVID-19 on clinical outcomes and allograft function in lung transplant (LTx) recipients are limited and based mainly on reports with short follow-up. In this nationwide study, all LTx recipients with COVID-19 diagnosed from 1 February 2020 to 30 April 2021 were included. The patients were followed until 1 August 2021 or death. We analysed demographics, clinical features, therapeutic management and outcomes, including lung function. Forty-seven patients were identified: median age was 59 (10-78) years, 53.1% were male, and median follow-up was 194 (23-509) days. COVID-19 was asymptomatic or mild at presentation in 48.9%. Nine patients (19.1%) were vaccinated pre-COVID infection. Two patients (4.3%) died within 28 days of testing positive, and the overall survival rate was 85.1%. The patients with asymptomatic or mild symptoms had a higher median % expected forced expiratory volume during the first second than the patients with worse symptoms (P = 0.004). LTx recipients develop the entire spectrum of COVID-19, and in addition to previously acknowledged risk factors, lower pre-COVID lung function was associated with more severe disease presentation.

Atrial natriuretic peptide does not degrade the endothelial glycocalyx: A secondary analysis of a randomized porcine model.

BACKGROUND: The atrial natriuretic peptide (ANP) released from the heart regulates intravascular volume and is suspected to increase capillary permeability. Contradictory results regarding ANP and glycocalyx degradation have been reported. The aim of this study was to investigate if an infusion of ANP causes degradation of the endothelial glycocalyx. METHODS: Twenty pigs, pretreated with 250 mg methylprednisolone, were randomized to receive an infusion of either ANP (50 ng/kg/min) (n = 10) or 0.9% NaCl (n = 10) during 60 min. Endothelial glycocalyx components (heparan sulphate proteoglycan and hyaluronic acid), Hct, calculated plasma volume and colloid osmotic pressure were measured from baseline to 60 min. RESULTS: There was no difference between the control and intervention groups for heparan sulphate proteoglycan and hyaluronic acid corrected for the change in plasma volume (P = .333 and 0.197). Hct increased with 1.8 ± 2.2% in the intervention group (P = .029) with no change -0.5 ± 2.3% in the control group (P = .504). The plasma volume decreased in the intervention group with -8.4 ± 10% (P = .034) with no change in the control group 3.1 ± 12% (P = .427). Median changes in colloid osmotic pressures in the control and intervention group were -0.39 [95% CI, -1.88-0.13] and 0.9 [95% CI, 0.00-1.58], respectively (P = .012). CONCLUSIONS: In this randomized porcine study, an ANP infusion did not cause endothelial glycocalyx degradation but decreased the plasma volume most probably due to precapillary vasodilation and increased filtration.

Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model's applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.

Crosstalk between Mast Cells and Lung Fibroblasts Is Modified by Alveolar Extracellular Matrix and Influences Epithelial Migration.

Mast cells play an important role in asthma, however, the interactions between mast cells, fibroblasts and epithelial cells in idiopathic pulmonary fibrosis (IPF) are less known. The objectives were to investigate the effect of mast cells on fibroblast activity and migration of epithelial cells. Lung fibroblasts from IPF patients and healthy individuals were co-cultured with LAD2 mast cells or stimulated with the proteases tryptase and chymase. Human lung fibroblasts and mast cells were cultured on cell culture plastic plates or decellularized human lung tissue (scaffolds) to create a more physiological milieu by providing an alveolar extracellular matrix. Released mediators were analyzed and evaluated for effects on epithelial cell migration. Tryptase increased vascular endothelial growth factor (VEGF) release from fibroblasts, whereas co-culture with mast cells increased IL-6 and hepatocyte growth factor (HGF). Culture in scaffolds increased the release of VEGF compared to culture on plastic. Migration of epithelial cells was reduced by IL-6, while HGF and conditioned media from scaffold cultures promoted migration. In conclusion, mast cells and tryptase increased fibroblast release of mediators that influenced epithelial migration. These data indicate a role of mast cells and tryptase in the interplay between fibroblasts, epithelial cells and the alveolar extracellular matrix in health and lung disease.

Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo.

Transcriptional studies of the human heart provide insight into physiological and pathophysiological mechanisms, essential for understanding the fundamental mechanisms of normal cardiac function and how they are altered by disease. To improve the understanding of why men and women may respond differently to the same therapeutic treatment it is crucial to learn more about sex-specific transcriptional differences. In this study the transcriptome of right atrium and left ventricle was compared across sex and regional location. Paired biopsies from five male and five female patients undergoing aortic valve replacement or coronary artery bypass grafting were included. Gene expression analysis identified 620 differentially expressed transcripts in atrial and ventricular tissue in men and 471 differentially expressed transcripts in women. In total 339 of these transcripts overlapped across sex but notably, 281 were unique in the male tissue and 162 in the female tissue, displaying marked sex differences in the transcriptional machinery. The transcriptional activity was significantly higher in atrias than in ventricles as 70% of the differentially expressed genes were upregulated in the atrial tissue. Furthermore, pathway- and functional annotation analyses performed on the differentially expressed genes showed enrichment for a more heterogeneous composition of biological processes in atrial compared with the ventricular tissue, and a dominance of differentially expressed genes associated with infection disease was observed. The results reported here provide increased insights about transcriptional differences between the cardiac atrium and ventricle but also reveal transcriptional differences in the human heart that can be attributed to sex.

A Possible Mechanism behind Faster Clearance and Higher Peak Concentrations of Cardiac Troponin I Compared with Troponin T in Acute Myocardial Infarction.

BACKGROUND: Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). METHODS: We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. RESULTS: Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. CONCLUSION: Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.