Publications by authors named "Göran Dellgren"

96 Publications

Impaired Differentiation of COPD Bronchial Epithelial Cells Grown on Bronchial Scaffolds.

Am J Respir Cell Mol Biol 2021 Apr 21. Epub 2021 Apr 21.

AstraZeneca, Gothenburg, Sweden;

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation, small airway remodeling and emphysema. Airway remodeling in COPD patients 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 and normal human bronchial epithelial cells (HBEC) after repopulation on decellularized bronchial scaffolds derived from COPD patients or non-COPD donors. 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, while 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 compared to normal bronchial scaffolds. Mass spectrometry identified thirteen matrisome proteins as differentially abundant between COPD 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. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1165/rcmb.2019-0395OCDOI Listing
April 2021

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

Int J Mol Sci 2021 Jan 6;22(2). Epub 2021 Jan 6.

Unit of Lung Biology, Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden.

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.
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http://dx.doi.org/10.3390/ijms22020506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825515PMC
January 2021

History of cancer and survival after coronary artery bypass grafting: Experiences from the SWEDEHEART registry.

J Thorac Cardiovasc Surg 2020 Sep 17. Epub 2020 Sep 17.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objective: To explore the currently unknown association between history of cancer at the time of coronary artery bypass grafting (CABG) and long-term survival.

Methods: All patients (n = 82,137) undergoing isolated first-time CABG in Sweden during 1997-2015 were included in this retrospective population-based cohort study. Individual patient data from the SWEDEHEART registry and 4 other mandatory nationwide health care registries were merged. Multivariable Cox proportional hazards regression and competing risk models adjusted for age and gender were used to assess associations between history of cancer, and long-term all-cause, cardiovascular and cancer mortality. Median follow-up was 9.0 years (interquartile range, 4.8-13.1).

Results: Altogether, 6819 (8.3%) of the patients had a history of cancer. The annual prevalence increased from 3.8% in 1997 to 14.8% in 2015. Patients with a history of cancer were older (72 vs 66 years; P < .001) and had more comorbidities. Long-term all-cause mortality was significantly greater in patients with a history of cancer (45.7% vs 22.9% at 10 years; adjusted hazard ratio, 1.33; 95% confidence interval [CI], 1.28-1.38, P < .001). According to the competing risk models, history of cancer was associated with an increased risk for cancer death (subdistribution hazard ratio, 2.45; 95% CI, 2.28-2.63, P < .001) but not cardiovascular death (subdistribution hazard ratio, 0.88; 95% CI, 0.83-0.94, P < .001).

Conclusions: The proportion of patients undergoing CABG with a history of cancer has increased over time. History of cancer at the time of surgery is associated with increased cancer deaths over time but not cardiovascular deaths. The same cardiovascular prognosis after CABG can be expected regardless of cancer history.
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http://dx.doi.org/10.1016/j.jtcvs.2020.09.043DOI Listing
September 2020

[Lungtransplantation in Sweden - over 1 200 patients transplanted since 1990].

Lakartidningen 2020 08 10;117. Epub 2020 Aug 10.

adjungerad professor, universitetsöverläkare, Transplantationscentrum, Sahlgrenska universitetssjukhuset.

Lung transplantation is an accepted treatment for end stage lung diseases and performed at two national centers in Sweden - Gothenburg and Lund. Since the start in 1990 over 1 200 patients have been transplanted.  The indications are severe progressive lung diseases with short expected survival or severe negative effects on daily life. There are several contraindications among which severe other organ disease, recent malignancy or psychiatric disease are most important.  The most common causes for lung transplantation are chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease, cystic fibrosis and pulmonary hypertension.  Long term survival after 5 years is 63 %, and after 10 years 48 %, which is better than the results reported in the international registry (57 % and 36 % respectively).   Lung transplantation is today a therapy for end stage pulmonary diseases with acceptable survival results. It is likely that the number of patients will increase in the future.
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August 2020

Durable circulatory support with a paracorporeal device as an option for pediatric and adult heart failure patients.

J Thorac Cardiovasc Surg 2021 Apr 15;161(4):1453-1464.e4. Epub 2020 May 15.

Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objectives: Not all patients in need of durable mechanical circulatory support are suitable for a continuous-flow left ventricular assist device. We describe patient populations who were treated with the paracorporeal EXCOR, including children with small body sizes, adolescents with complex congenital heart diseases, and adults with biventricular failure.

Methods: Information on clinical data, echocardiography, invasive hemodynamic measurements, and surgical procedures were collected retrospectively. Differences between various groups were compared.

Results: Between 2008 and 2018, a total of 50 patients (21 children and 29 adults) received an EXCOR as bridge to heart transplantation or myocardial recovery. The majority of patients had heart failure compatible with Interagency Registry for Mechanically Assisted Circulatory Support profile 1. At year 5, the overall survival probability for children was 90%, and for adults 75% (P = .3). After we pooled data from children and adults, the survival probability between patients supported by a biventricular assist device was similar to those treated with a left ventricular assist device/ right ventricular assist device (94% vs 75%, respectively, P = .2). Patients with dilated cardiomyopathy had a trend toward better survival than those with other heart failure etiologies (92% vs 70%, P = .05) and a greater survival free from stroke (92% vs 64%, P = .01). Pump house exchange was performed in nine patients due to chamber thrombosis (n = 7) and partial membrane rupture (n = 2). There were 14 cases of stroke in eleven patients.

Conclusions: Despite severe illness, patient survival on EXCOR was high, and the long-term overall survival probability following heart transplantation and recovery was advantageous. Treatment safety was satisfactory, although still hampered by thromboembolism, mechanical problems, and infections.
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http://dx.doi.org/10.1016/j.jtcvs.2020.04.163DOI Listing
April 2021

Haemophagocytic lymphohistiocytosis after heart transplantation: a case report.

Eur Heart J Case Rep 2020 Jun 3;4(3):1-4. Epub 2020 May 3.

Department of Transplant Institute, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden.

Background: Haemophagocytic lymphohistiocytosis (HLH) is an uncommon but serious systemic inflammatory response with high mortality rates. It can be triggered by malignancy or infectious agents, often in the context of immunosuppression. Literature covering HLH in heart transplantation (HTx) is scarce.

Case Summary: A 25-year-old male with a history of celiac disease underwent HTx at Sahlgrenska Hospital in 2011 due to giant cell myocarditis and was treated with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. He developed several episodes of acute cellular rejections (ACR) during the first 3 post-HTx years, which subsided after addition of everolimus. In May 2017, the patient was admitted to the hospital due to fever without focal symptoms. He had an extensive inflammatory reaction, but screening for infectious agents was negative. Haemophagocytic lymphohistiocytosis was discussed early, but first dismissed since two bone marrow biopsies revealed no signs of haemophagocytosis. Increasing levels of soluble IL-2 were considered confirmative of the diagnosis. Even with intense immunosuppressant treatment, the patient deteriorated and died in progressive multiorgan failure within 2 weeks of the symptom onset.

Discussion: A 25-year-old HTx recipient with an extensive inflammatory response, fulfilled criteria for HLH, but the diagnosis was delayed due to normal bone marrow biopsies. A background with autoimmune reactivity and immunosuppressive therapy may have contributed to HLH, but the actual trigger was not identified. Haemophagocytic lymphohistiocytosis can occur in HTx recipients in the absence of malignancy, identifiable infectious triggers and signs of haemophagocytosis. Early diagnosis and intervention are likely to be of importance for a favourable outcome.
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http://dx.doi.org/10.1093/ehjcr/ytaa070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319853PMC
June 2020

Donor heart and lung procurement: A consensus statement.

J Heart Lung Transplant 2020 06 21;39(6):501-517. Epub 2020 Apr 21.

Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.

Heart and lung procurements are multiphased processes often accompanied by an array of complex logistics. Approaches to donor evaluation and management, organ procurement, and organ preservation vary among individual procurement teams. Because early graft failure remains a major cause of mortality in contemporary thoracic organ transplant recipients, we sought to establish some standardization in the procurement process. This paper, in this vein, represents an international consensus statement on donor heart and lung procurement and is designed to serve as a guide for physicians, surgeons, and other providers who manage donors to best optimize the clinical status for the procurement of both heart and lungs for transplantation. Donation after brain death (DBD) and donation after circulatory determination death (referred to as donation after circulatory death [DCD] for the remainder of the paper) for both heart and lung transplantation will be discussed in this paper. Although the data available on DCD heart donation are limited, information regarding the surgical technique for procurement is included within this consensus statement. Furthermore, this paper will focus on adult DBD and DCD heart and lung procurement. Currently, no certification, which is either recognized and/or endorsed by the transplant community at large, exists for the training of a cardiothoracic procurement surgeon. Nevertheless, establishing a training curriculum and credentialing requirements are beyond the scope of this paper.
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http://dx.doi.org/10.1016/j.healun.2020.03.020DOI Listing
June 2020

Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients: Design of the randomized controlled EVOLVD trial.

Clin Transplant 2020 09 6;34(9):e13984. Epub 2020 Aug 6.

Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Cardiac allograft vasculopathy (CAV) is characterized by diffuse thickening of the arterial intima. Statins reduce the incidence of CAV, but despite the use of statins, CAV remains one of the leading causes of long-term death after heart transplant. Inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce cholesterol levels but have not been tested in heart transplant recipients.

Methods: The Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients (EVOLVD) trial (ClinicalTrials.gov Identifier: NCT03734211) is a randomized, double-blind trial designed to test the effect of the PCSK9 inhibitor evolocumab on coronary intima thickness in heart transplant recipients. Adults who have received a cardiac transplant within the past 4-8 weeks are eligible. Exclusion criteria include an estimated glomerular filtration rate < 20 mL/min/1.73 m , renal replacement therapy, or contraindications to coronary angiography with intravascular ultrasound. 130 patients will be randomized (1:1) to 12-month treatment with evolocumab or matching placebo. The primary endpoint is the coronary artery intima thickness as measured by intravascular ultrasound.

Conclusion: The EVOLVD trial is a randomized clinical trial designed to show whether treatment with the PCSK9 inhibitor evolocumab can ameliorate CAV over the first year after heart transplant.
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http://dx.doi.org/10.1111/ctr.13984DOI Listing
September 2020

Dextran- Versus Crystalloid-Based Prime in Cardiac Surgery: A Prospective Randomized Pilot Study.

Ann Thorac Surg 2020 11 14;110(5):1541-1547. Epub 2020 Apr 14.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address:

Background: The optimum priming fluid for the cardiopulmonary bypass (CPB) circuit is still debated. We compared a new hyperoncotic priming solution containing dextran 40, which has an electrolyte composition that mimics extracellular fluid, with a standard crystalloid-based prime.

Methods: Eighty cardiac surgery patients were included in this double-blind, randomized, single-center study. Patients were randomized to either a dextran-based prime or a crystalloid prime containing Ringer's acetate and mannitol. The primary end point was colloid oncotic pressure in serum during CPB. Secondary end points included fluid balance, bleeding and transfusion requirements, pulmonary function, hemolysis, systemic inflammation, and markers of renal, hepatic, myocardial, and brain injury. Blood samples were collected before, during, and after CPB.

Results: Colloid oncotic pressure was higher in the dextran group than in the crystalloid prime group during CPB (18.8 ± 2.9 versus 16.4 ± 2.9 mm Hg; P < .001) and 10 minutes after CPB (19.2 ± 2.7 versus 16.8 ± 2.9 mm Hg; P < .001). Patients in the dextran group required less intravenous fluid during CPB (1090 ± 499 versus 1437 ± 543 mL; P = .004) and net fluid balance was less positive 12 hours after surgery (1431 ± 741 versus 1901 ± 922 mL; P = .014). Plasma-free hemoglobin was significantly lower in the dextran group 2 hours after CPB (0.18 ± 0.11 versus 0.41 ± 0.33; P = .001). There were no significant differences in bleeding, transfusion requirements, organ function, systemic inflammation, or brain and myocardial injury markers between groups at any time point.

Conclusions: Our results suggest that a hyperoncotic dextran-based priming solution preserves intraoperative colloid oncotic pressure compared with crystalloid prime. Larger studies with clinically valid end points are necessary to evaluate hyperoncotic prime solutions further.
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http://dx.doi.org/10.1016/j.athoracsur.2020.03.031DOI Listing
November 2020

Randomized trial of a left ventricular assist device as destination therapy versus guideline-directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial.

Eur J Heart Fail 2020 04 26;22(4):739-750. Epub 2020 Feb 26.

Departments of Cardiothorax Surgery and Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden.

Aims: Patients with advanced heart failure (AdHF) who are ineligible for heart transplantation (HTx) can become candidates for treatment with a left ventricular assist device (LVAD) in some countries, but not others. This reflects the lack of a systematic analysis of the usefulness of LVAD systems in this context, and of their benefits, limitations and cost-effectiveness. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) study is a Phase IV, prospective, 1:1 randomized, non-blinded, multicentre trial that will examine the impact of assignment to mechanical circulatory support with guideline-directed LVAD destination therapy (GD-LVAD-DT) using the HeartMate 3 (HM3) continuous flow pump vs. guideline-directed medical therapy (GDMT) on survival in a population of AdHF patients ineligible for HTx.

Methods: A total of 80 patients will be recruited to SweVAD at the seven university hospitals in Sweden. The study population will comprise patients with AdHF (New York Heart Association class IIIB-IV, INTERMACS profile 2-6) who display signs of poor prognosis despite GDMT and who are not considered eligible for HTx. Participants will be followed for 2 years or until death occurs. Other endpoints will be determined by blinded adjudication. Patients who remain on study-assigned interventions beyond 2 years will be asked to continue follow-up for outcomes and adverse events for up to 5 years.

Conclusion: The SweVAD study will compare survival, medium-term benefits, costs and potential hazards between GD-LVAD-DT and GDMT and will provide a valuable reference point to guide destination therapy strategies for patients with AdHF ineligible for HTx.
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http://dx.doi.org/10.1002/ejhf.1773DOI Listing
April 2020

Invasive haemodynamics in de novo everolimus vs. calcineurin inhibitor heart transplant recipients.

ESC Heart Fail 2020 04 14;7(2):567-576. Epub 2020 Feb 14.

Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Aims: Invasive haemodynamic profiles at rest and during exercise after heart transplantation (HTx) have never been described in a randomized trial where de novo everolimus (EVR)-based therapy with early calcineurin inhibitor (CNI) withdrawal has been compared with conventional CNI treatment. We report central invasive haemodynamic parameters at rest and exercise during a 3 year follow-up after HTx in a sub-study of the SCandiavian Heart transplant Everolimus De novo stUdy with earLy calcineurin inhibitor avoidancE trial. We hypothesized that the nephroprotective properties, the less development of cardiac allograft vasculopathy (CAV), and the antifibrotic properties of EVR, in comparison with CNI-based immunosuppression, would demonstrate favourable invasive haemodynamic profiles in patients at rest and during exercise.

Methods And Results: Ninety of 115 HTx recipients randomized to EVR or CNI treatment performed right heart catheterization at rest and 68 performed right heart catheterization at exercise up to 3 years after HTx. Haemodynamic profiles were compared between EVR and CNI treatment groups. Resting haemodynamics improved in both groups from pre-HTx to the first follow-up at 7-11 weeks post-HTx and thereafter remained unchanged up to 3 years of follow-up. During follow-up, cardiac reserve during exercise increased with higher levels of maximum heart rate (118 to 148 b.p.m., P < 0.001), mean arterial pressure (103 to 128 mmHg, P < 0.001), and cardiac output (10.3 to 12.2 l/min, P < 0.001). No significant differences in haemodynamic parameters were observed between the EVR and CNI groups at rest or exercise. Isolated post-capillary pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≥ 15 mmHg, and pulmonary vascular resistance <3) were measured in 11% of the patients at 7-11 weeks, 5% at 12 months, and 6% at 36 months after HTx. The EVR group had significantly better kidney function (76 mL/min/1 vs. 60 mL/min/1, P < 0.001) and reduced CAV (P < 0.01) but an increased rate of early biopsy-proven treated rejections (21.2% vs 5.7%, P < 0.01) compared with the CNI group at any time point. The differences in renal function, CAV, or early biopsy-proven treated acute rejections were not associated with altered haemodynamics.

Conclusions: De novo EVR treatment with early CNI withdrawal compared with conventional CNI therapy did not result in differences in haemodynamics at rest or during exercise up to 3 years after HTx despite significant differences in renal function, reduced CAV, and number of early biopsy-proven treated rejections.
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http://dx.doi.org/10.1002/ehf2.12608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160471PMC
April 2020

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

Clin Chem 2020 02;66(2):333-341

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

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.
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http://dx.doi.org/10.1093/clinchem/hvz003DOI Listing
February 2020

Design and Rationale of a Scandinavian Multicenter Randomized Study Evaluating if Once-Daily Tacrolimus Versus Twice-Daily Cyclosporine Reduces the 3-year Incidence of Chronic Lung Allograft Dysfunction After Lung Transplantation (ScanCLAD Study).

Adv Ther 2020 03 28;37(3):1260-1275. Epub 2020 Jan 28.

Transplant Institute, Sahlgrenska, University Hospital, Gothenburg, Sweden.

Background: A low level of evidence exists regarding the choice of calcineurin inhibitor (CNI) for immunosuppression after lung transplantation (LTx). Therefore, we designed a randomized clinical trial according to good clinical practice rules to compare tacrolimus with cyclosporine after LTx.

Methods: The ScanCLAD study is an investigator-initiated, pragmatic, controlled, randomized, open-label, multicenter study evaluating if an immunosuppressive protocol based on anti-thymocyte globulin (ATG) induction, once-daily tacrolimus dose, mycophenolate mofetil, and corticosteroid reduces the incidence of chronic lung allograft dysfunction (CLAD) after LTx, compared to a cyclosporine-based protocol with all other immunosuppressive and prophylactic drugs being identical between groups. All patients will be followed for 3 years to determine the main endpoint of CLAD. The study is designed for superiority, and power calculations show that 242 patients are needed. Also, the study is designed with more than 10 substudies addressing other important and unresolved issues in LTx. In addition, the ScanCLAD study enabled the synchronization of the treatment and follow-up protocols of the lung transplantation programs of all five Scandinavian lung transplantation centers.

Planned Outcomes: Recruitment started in 2016. At the end of April 2019, 227 patients were randomized. We anticipate the last patient to be randomized in autumn 2019, and thus the last patient visits will be in 2022. The ScanCLAD study is enrolling and investigates which CNI is to be preferred from a CLAD perspective after LTx.

Trial Registry Number: ScanCLAD trial registered at ClinicalTrials.gov before patient enrollment (NCT02936505). EUDRACT number 2015-004137-27.
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http://dx.doi.org/10.1007/s12325-020-01224-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089723PMC
March 2020

Mild acute cellular rejection and development of cardiac allograft vasculopathy assessed by intravascular ultrasound and coronary angiography in heart transplant recipients-a SCHEDULE trial substudy.

Transpl Int 2020 05 9;33(5):517-528. Epub 2020 Feb 9.

Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Substudy of the SCHEDULE trial (n = 115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. Seventy-six patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy-proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx. Median age was 53 years (45-61), and 71% were male. ACR was recorded in 67%, and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), and ≥2R (25%). Median ∆MIT (maximal intimal thickness) was not significantly different between groups (P = 0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MIT (r = -0.025, P = 0.83). The number of 1R was not a significant predictor of ∆MIT (P = 0.58), and no significant interaction with treatment was found (P = 0.98). The burden of mild ACR was not associated with CAV development.
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http://dx.doi.org/10.1111/tri.13577DOI Listing
May 2020

Extended use of extra corporeal membrane oxygenation as bridge to lung transplantation in two patients.

J Cardiothorac Surg 2020 Jan 13;15(1):16. Epub 2020 Jan 13.

Transplant Institute, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: We have previously reported our outcome after extra-corporeal membrane oxygenation as bridge-to-lung transplantation, which initially was considered controversial, but over time have gained acceptance and now is performed in most high-volume institutions.

Case Presentation: We now report two "extreme" extra-corporeal membrane oxygenation (ECMO) bridge-to-lung transplantation cases, on ECMO > 200 days prior to lung transplantation. One patient survived long-term and the other one did not, and clinical cause and morbidity is outlined in this case-report.

Conclusion: We believe these two cases highlight the medical, ethical and resource allocation difficulties involved with saving patients in very dire circumstances. We have shown that a patient can survive extremely long duration of ECMO bridge to lung transplantation, but selection remains crucial to achieve a reasonable cost-benefit.
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http://dx.doi.org/10.1186/s13019-020-1046-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958736PMC
January 2020

Mortality after tricuspid valve procedures: A 27-year, single-center experience.

J Thorac Cardiovasc Surg 2021 04 15;161(4):1239-1248.e1. Epub 2019 Oct 15.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objective: To assess mortality after tricuspid valve (TV) surgery in a large single-center patient cohort.

Methods: Data from 392 TV procedures performed between 1989 and 2015 in 388 adult patients were retrospectively reviewed. The patients were divided into groups according to the type of concomitant procedure, ie, coronary artery bypass grafting (CABG) (TV + CABG group; n = 87), other valve surgery (TV + valve group; n = 240), or an isolated TV procedure with or without another minor procedure (isolated TV group; n = 65), and the era of the operation, ie, 1989-2005 (n = 173) or 2006-2015 (n = 219). Control groups of patients who underwent other valve procedures and/or CABG during the same time periods were used for comparison.

Results: During the most recent era, the annual number of TV procedures increased 2.4-fold, mainly for TV + valve procedures (2.8-fold). Within the TV + valve group, a larger proportion of patients had mild-to-moderate tricuspid regurgitation (grade ≤2) compared with the first-time period (P = .001). The TV + CABG group had significantly greater mortality than both the other groups during both time periods, whereas isolated TV procedure had the lowest mortality rates with the exception of the TV + valve group during the most recent era (P = .41). Survival for patients undergoing TV + valve procedures has improved significantly during the last decade (P = .001) and was comparable with that for other valve operations during this period.

Conclusions: In the last decade, TV repair has been performed more frequently and at lower grades of tricuspid regurgitation compared with previously, and mortality after TV procedures has decreased.
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http://dx.doi.org/10.1016/j.jtcvs.2019.09.155DOI Listing
April 2021

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

Physiol Genomics 2020 02 23;52(2):110-120. Epub 2019 Dec 23.

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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.
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http://dx.doi.org/10.1152/physiolgenomics.00036.2019DOI Listing
February 2020

Early post-transplant elevated pulmonary artery pressure predicts adverse outcome in cardiac recipients.

Int J Cardiol Heart Vasc 2020 Feb 19;26:100438. Epub 2019 Nov 19.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.

Aim: To investigate the prognostic value of early post-transplant hemodynamic measurements on 5-year mortality in cardiac recipients (HTx).

Methods: A right heart catheterization was performed in 290 heart transplantation (HTx) recipients at a one-year post-HTx evaluation. To study the effect of post-HTx hemodynamic variables on 5-year outcome, the cohort was stratified into several subgroups. For right atrial pressure (RAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), and pulmonary vascular resistance (PVR), patients with values from the upper 10th percentile (high), were compared with those with values from the remaining lower 90th percentile (normal). For cardiac index (CI), patients with values from the lower 10th percentile (low) were compared with those with values from the remaining upper 90th percentile (normal).

Results: Death or re-transplantation within 5 years after the one-year control occurred in 44 patients (13%). Of those, death or re-HTx was related to graft failure in 20 of cases (45%) and non-cardiac causes in 24 of cases (55%). The risk of death or re-HTx was higher in the subgroup with MPAP above 23 mmHg than those equal to or below this value [hazard ratio 3.22, 95% confidence interval (CI) 1.49-6.97;  = 0.003]. The association remained significant despite adjustment for several comorbidities. There were no differences in outcome between subgroups stratified with respect to high versus low RAP, PAWP, CI or PVR.

Conclusion: Elevated pulmonary artery pressure at a first annual evaluation after HTx was the only hemodynamic variable that predicted impaired outcome in cardiac recipients.
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http://dx.doi.org/10.1016/j.ijcha.2019.100438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872849PMC
February 2020

Effects of atrial natriuretic peptide on renal function during cardiopulmonary bypass: a randomized pig model.

Eur J Cardiothorac Surg 2020 04;57(4):652-659

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objectives: Acute kidney injury is a well-known complication after cardiac surgery and cardiopulmonary bypass (CPB). In this experimental animal study, we evaluated the effects of atrial natriuretic peptide (ANP) on renal function, perfusion, oxygenation and tubular injury during CPB.

Methods: Twenty pigs were blindly randomized to continuous infusion of either ANP (50 ng/kg/min) or placebo before, during and after CPB. Renal blood flow as well as cortical and medullary perfusion was measured. Blood was repeatedly sampled from the renal vein. Glomerular filtration rate was measured by infusion clearance of 51Cr-EDTA.

Results: Glomerular filtration rate was higher (P < 0.001), whereas renal blood flow or renal oxygen delivery was not affected by ANP during CPB. Renal oxygen consumption did not differ between groups during CPB, whereas renal oxygen extraction was higher in the ANP group (P = 0.03). Urine flow and sodium excretion were higher in the ANP group during CPB. Blood flow in the renal medulla, but not in the cortex, dropped during CPB, an effect that was not seen in the animals that received ANP.

Conclusions: ANP improved renal function during CPB. Despite impaired renal oxygenation, ANP did not cause tubular injury, suggesting a renoprotective effect of ANP during CPB. Also, CPB induced a selectively reduced blood flow in the renal medulla, an effect that was counteracted by ANP.
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http://dx.doi.org/10.1093/ejcts/ezz297DOI Listing
April 2020

Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage.

J Clin Endocrinol Metab 2020 02;105(2)

Department of Pathology and Genetics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Context: Glycogenin is considered to be an essential primer for glycogen biosynthesis. Nevertheless, patients with glycogenin-1 deficiency due to biallelic GYG1 (NM_004130.3) mutations can store glycogen in muscle. Glycogenin-2 has been suggested as an alternative primer for glycogen synthesis in patients with glycogenin-1 deficiency.

Objective: The objective of this article is to investigate the importance of glycogenin-1 and glycogenin-2 for glycogen synthesis in skeletal and cardiac muscle.

Design, Setting, And Patients: Glycogenin-1 and glycogenin-2 expression was analyzed by Western blot, mass spectrometry, and immunohistochemistry in liver, heart, and skeletal muscle from controls and in skeletal and cardiac muscle from patients with glycogenin-1 deficiency.

Results: Glycogenin-1 and glycogenin-2 both were found to be expressed in the liver, but only glycogenin-1 was identified in heart and skeletal muscle from controls. In patients with truncating GYG1 mutations, neither glycogenin-1 nor glycogenin-2 was expressed in skeletal muscle. However, nonfunctional glycogenin-1 but not glycogenin-2 was identified in cardiac muscle from patients with cardiomyopathy due to GYG1 missense mutations. By immunohistochemistry, the mutated glycogenin-1 colocalized with the storage of glycogen and polyglucosan in cardiomyocytes.

Conclusions: Glycogen can be synthesized in the absence of glycogenin, and glycogenin-1 deficiency is not compensated for by upregulation of functional glycogenin-2. Absence of glycogenin-1 leads to the focal accumulation of glycogen and polyglucosan in skeletal muscle fibers. Expression of mutated glycogenin-1 in the heart is deleterious, and it leads to storage of abnormal glycogen and cardiomyopathy.
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http://dx.doi.org/10.1210/clinem/dgz075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046021PMC
February 2020

Outcome after heart-lung or lung transplantation in patients with Eisenmenger syndrome.

Heart 2020 01 21;106(2):127-132. Epub 2019 Aug 21.

Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

Objective: The optimal timing for transplantation is unclear in patients with Eisenmenger syndrome (ES). We investigated post-transplantation survival and transplantation-specific morbidity after heart-lung transplantation (HLTx) or lung transplantation (LTx) in a cohort of Nordic patients with ES to aid decision-making for scheduling transplantation.

Methods: We performed a retrospective, descriptive, population-based study of patients with ES who underwent transplantation from 1985 to 2012.

Results: Among 714 patients with ES in the Nordic region, 63 (9%) underwent transplantation. The median age at transplantation was 31.9 (IQR 21.1-42.3) years. Within 30 days after transplantation, seven patients (11%) died. The median survival was 12.0 (95% CI 7.6 to 16.4) years and the overall 1-year, 5-year, 10-year and 15-year survival rates were 84.1%, 69.7%, 55.8% and 40.6%, respectively. For patients alive 1 year post-transplantation, the median conditional survival was 14.8 years (95% CI 8.0 to 21.8), with 5-year, 10-year and 15-year survival rates of 83.3%, 67.2% and 50.0%, respectively. There was no difference in median survival after HLTx (n=57) and LTx (n=6) (14.9 vs 10.6 years, p=0.718). Median cardiac allograft vasculopathy, bronchiolitis obliterans syndrome and dialysis/kidney transplantation-free survival rates were 11.2 (95% CI 7.8 to 14.6), 6.9 (95% CI 2.6 to 11.1) and 11.2 (95% CI 8.8 to 13.7) years, respectively. The leading causes of death after the perioperative period were infection (36.7%), bronchiolitis obliterans syndrome (23.3%) and heart failure (13.3%).

Conclusions: This study shows that satisfactory post-transplantation survival, comparable with contemporary HTx and LTx data, without severe comorbidities such as cardiac allograft vasculopathy, bronchiolitis obliterans syndrome and dialysis, is achievable in patients with ES, with a conditional survival of nearly 15 years.
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http://dx.doi.org/10.1136/heartjnl-2019-315345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993032PMC
January 2020

Left ventricular dysfunction in potential heart donors and its influence on recipient outcomes.

J Thorac Cardiovasc Surg 2020 04 11;159(4):1333-1341.e6. Epub 2019 Jul 11.

Transplant Institute, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden.

Objectives: New onset of left ventricular (LV) dysfunction in organ donors is frequent and considered as a contraindication for utilization of the heart. However, such dysfunction might be caused by sympathetic stress and could be transient (Takotsubo syndrome). In this study, we assessed the incidence, pattern, and predictors of LV dysfunction in potential heart donors and evaluated its influence on recipient outcomes.

Methods: Donor records of consecutive organ donors in western Sweden between 2006 and 2016 were reviewed. Recipients of transplanted donor hearts were identified in the Scandiatransplant database.

Results: Of 641 potential heart donors who underwent echocardiographic assessment, LV dysfunction (ejection fraction <50% and/or regional hypokinesia) was found in 155 donors (24%). Regional hypokinesia was seen in 113 donors of whom 46 had a Takotsubo-like circumferential hypokinetic pattern. Independent donor variables associated with LV dysfunction were a younger age, cardiac arrest as a contributing factor to death, need for inotropic support, and a shorter time from admission to declaration of brain death. A total of 338 (54%) donor hearts were transplanted, of which 45 (14%) had LV dysfunction. LV dysfunction was a major determinant of not transplanting the heart (P < .001). After transplantation, LV function normalized in the recipients. Neither short-term outcomes nor the composite end point of death or retransplantation over time differed between recipients of donor hearts with versus without LV dysfunction (P = .587).

Conclusions: LV dysfunction is common among potential heart donors. These hearts were safely transplanted in this study. The use of these hearts might significantly increase transplantation rates.
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http://dx.doi.org/10.1016/j.jtcvs.2019.06.070DOI Listing
April 2020

Matrisome Properties of Scaffolds Direct Fibroblasts in Idiopathic Pulmonary Fibrosis.

Int J Mol Sci 2019 Aug 17;20(16). Epub 2019 Aug 17.

Lung Biology, Department of Experimental Medical Sciences, Lund University, BMC C12, Lund 221 84, Sweden.

In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). Scaffolds were repopulated with healthy fibroblasts cultured under static stretch with heavy isotope amino acids (SILAC), to examine newly synthesized proteins over time. IPF scaffolds were characterized by increased tissue density, stiffness, ultimate force, and differential expressions of matrisome proteins compared to healthy scaffolds. Collagens, proteoglycans, and ECM glycoproteins were increased in IPF scaffolds, however while specific basement membrane (BM) proteins such as laminins and collagen IV were decreased, nidogen-2 was also increased. Findings were confirmed with histology, clearly showing a disorganized BM. Fibroblasts produced scaffold-specific proteins mimicking preexisting scaffold composition, where 11 out of 20 BM proteins were differentially expressed, along with increased periostin and proteoglycans production. We demonstrate how matrisome changes affect fibroblast activity using novel approaches to study temporal differences, where IPF scaffolds support a disorganized BM and upregulation of disease-associated proteins. These matrix-directed cellular responses emphasize the IPF matrisome and specifically the BM components as important factors for disease progression.
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http://dx.doi.org/10.3390/ijms20164013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719040PMC
August 2019

The carnitine-butyrobetaine-TMAO pathway after cardiac transplant: Impact on cardiac allograft vasculopathy and acute rejection.

J Heart Lung Transplant 2019 10 19;38(10):1097-1103. Epub 2019 Jun 19.

Research Institute of Internal Medicine; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway.

Background: Alterations in the partly microbiota-dependent carnitine-γ-butyrobetaine (γBB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection.

Methods: We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound.

Results: Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant.

Conclusions: Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.
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http://dx.doi.org/10.1016/j.healun.2019.06.003DOI Listing
October 2019

Sound analysis of the magnetically levitated left ventricular assist device HeartMate 3.

Int J Artif Organs 2019 Dec 28;42(12):717-724. Epub 2019 Jun 28.

Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

Introduction: The HeartMate 3 has shown lower rates of adverse events compared to previous devices due to the design and absence of mechanical bearings. For previous devices, sound analysis emerged as a way to assess pump function. The aims of this study were to determine if sound analysis can be applied to the HeartMate 3 in vivo and in vitro and to evaluate an electronic stethoscope.

Method: Sound recordings were performed with microphones and clinical accessible electronic stethoscope. The recordings were studied in both the time and the frequency domains. Recordings from four patients were performed to determine if in vivo and in vitro recordings are comparable.

Results: The results show that it is possible to detect sound from HeartMate 3 and the sound spectrum is clear. Pump frequency and frequency of the pulsatile mode are easily determined. Frequency spectra from in vitro and in vivo recordings have the same pattern, and the major proportion (96.7%) of signal power is located at the pump speed frequency ±40 Hz. The recordings from the patients show low inter-individual differences except from location of peaks originating from pump speed and harmonics. Electronic stethoscopes could be used for sound recordings, but the dedicated equipment showed a clearer sound spectrum.

Discussion: The results show that acoustic analysis can also be performed with the HeartMate 3 and that in vivo and in vitro sound spectrum is similar. The frequency spectra are different from previous devices, and methods for assessing pump function or thrombosis need further evaluation.
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http://dx.doi.org/10.1177/0391398819857443DOI Listing
December 2019

The Atrioventricular Junction: A Potential Niche Region for Progenitor Cells in the Adult Human Heart.

Stem Cells Dev 2019 08 27;28(16):1078-1088. Epub 2019 Jun 27.

1Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden.

A stem cell niche is a microenvironment where stem cells reside in a quiescent state, until activated. In a previous rat model, we combined 5-bromo-2-deoxy-uridine labeling with activation of endogenous stem cells by physical exercise and revealed a distinct region, in the atrioventricular junction (AVj), with features of a stem cell niche. In this study, we aim to investigate whether a similar niche exists in the human heart. Paired biopsies from AVj and left ventricle (LV) were collected both from explanted hearts of organ donors, not used for transplantation ( = 7) and from severely failing hearts from patients undergoing heart transplantation ( = 7). Using antibodies, we investigated the expression of stem cell, hypoxia, proliferation and migration biomarkers. In the collagen-dense region of the AVj in donor hearts, progenitor markers, MDR1, SSEA4, ISL1, WT1, and hypoxia marker, HIF1-α, were clearly detected. The expression gradually decreased with distance from the valve. At the myocardium border in the AVj costaining of the proliferation marker Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac Troponin-T (cTnT) indicated proliferation of small cardiomyocytes. In the same site we also detected ISL1/WT1/cTnT cells. In addition, heterogeneity in cardiomyocyte sizes was noted. Altogether, these findings indicate different developmental stages of cardiomyocytes below the region dense in stem cell marker expression. In patients suffering from heart failure the AVj region showed signs of impairment generally displaying much weaker or no expression of progenitor markers. We describe an anatomic structure in the human hearts, with features of a progenitor niche that coincided with the same region previously identified in rats with densely packed cells expressing progenitor and hypoxia markers. The data provided in this study indicate that the adult heart contains progenitor cells and that AVj might be a specific niche region from which the progenitors migrate at the time of regeneration.
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http://dx.doi.org/10.1089/scd.2019.0075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686725PMC
August 2019

Outcomes and Long-term Survival After Pulmonary Retransplantation: A Single-Center Experience.

Ann Thorac Surg 2019 10 20;108(4):1037-1044. Epub 2019 May 20.

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: The median survival after lung retransplantation (ReLTx) reported to the International Society of Heart and Lung Transplantation is restricted to 2.5 years. We report the results after ReLTx from our center.

Methods: A retrospective data collection was performed for the 635 patients who underwent lung transplantation between 1991 and 2017 at our center. Recipient variables were compared between patients undergoing only primary lung transplantation (PLTx) and those undergoing PLTx and later ReLTx. Time to death was compared using the Kaplan-Meier method. The risk of ReLTx was analyzed in Cox regression models. Any interaction between type of transplantation, single/double, and PLTx/ReLTx was investigated.

Results: ReLTx was performed in 49 patients. Survival after ReLTx at 30 days and 1, 2, and 5 years was 90%, 76%, 71%, and 55%, respectively, and the corresponding survival after PLTx was 94%, 82%, 76%, and 61%, respectively. A hazard ratio of 1.73 for ReLTx was shown (95% confidence interval [CI], 1.14 to 2.63; P = .011). After adjustments for sex, age, diabetes, renal function, preoperative ventilator, and extracorporeal membrane oxygenation, the hazard ratio was 1.43 (95% CI, 0.90 to 2.26; P = .13). ReLTx was performed in 8 patients (16%) within the first year after PLTx. The 1-year survival for this group was 50% compared with 81% (P = .18) for patients who underwent ReLTx later than 1 year after the PLTx. One-year survival after double ReLTx was 60% (95% CI, 25% to 83%) compared with 79% (95% CI, 63% to 89%) for single ReLTx.

Conclusions: ReLTx is a reasonable option for a selected group of patients. Ideally, a number of well-established risk factors are avoided and the ReLTx is performed more than 1 year after the PLTx.
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http://dx.doi.org/10.1016/j.athoracsur.2019.04.028DOI Listing
October 2019

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Long-term Follow-up From the Randomized SCHEDULE Study.

Transplantation 2020 01;104(1):154-164

Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Background: A calcineurin inhibitor (CNI)-free immunosuppressive regimen has been demonstrated to improve renal function early after heart transplantation, but long-term outcome of such a strategy has not been well described.

Methods: In the randomized SCHEDULE trial, de novo heart transplant recipients received (1) everolimus with reduced-exposure CNI (cyclosporine) followed by CNI withdrawal at week 7-11 posttransplant or (2) standard-exposure cyclosporine, both with mycophenolate mofetil and corticosteroids; 95/115 randomized patients were followed up at 5-7 years posttransplant.

Results: Mean measured glomerular filtration rate was 74.7 mL/min and 62.4 mL/min with everolimus and CNI, respectively. The mean difference was in favor of everolimus by 11.8 mL/min in the intent-to-treat population (P = 0.004) and 17.2 mL/min in the per protocol population (n = 75; P < 0.001). From transplantation to last follow-up, the incidence of biopsy-proven acute rejection (BPAR) was 77% (37/48) and 66% (31/47) (P = 0.23) with treated BPAR in 50% and 23% (P < 0.01) in the everolimus and CNI groups, respectively; no episode led to hemodynamic compromise. Coronary allograft vasculopathy (CAV) assessed by coronary intravascular ultrasound was present in 53% (19/36) and 74% (26/35) of everolimus- and CNI-treated patients, respectively (P = 0.037). Graft dimensions and function were similar between the groups. Late adverse events were comparable.

Conclusions: These results suggest that de novo heart transplant patients randomized to everolimus and low-dose CNI followed by CNI-free therapy maintain significantly better long-term renal function as well as significantly reduced CAV than patients randomized to standard CNI treatment. Increased BPAR in the everolimus group during year 1 did not impair long-term graft function.
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http://dx.doi.org/10.1097/TP.0000000000002702DOI Listing
January 2020

Continuous-flow LVADs in the Nordic countries: complications and mortality and its predictors.

Scand Cardiovasc J 2019 02 5;53(1):14-20. Epub 2019 Mar 5.

j Department of Medicine , Karolinska Institutet and Heart and Vascular Theme, Karolinska University Hospital , Stockholm , Sweden.

Objectives: The purpose of this study was to assess complications and mortality and its predictors, with continuous-flow left ventricular assist devices (CF-LVADs) in the Nordic Countries.

Design: This was a retrospective, international, multicenter cohort study.

Results: Between 1993 and 2013, 442 surgically implanted long-term mechanical assist devices were used among 8 centers in the Nordic countries. Of those, 238 were CF-LVADs (HVAD or HeartMate II) implanted in patients >18 years with complete data. Postoperative complications and survival were compared and Cox proportion hazard regression analysis was used to identify predictors of mortality. The overall Kaplan-Meier survival rate was 75% at 1 year, 69% at 2 years and 63% at 3 years. A planned strategy of destination therapy had poorer survival compared to a strategy of bridge to transplantation or decision (2-year survival of 41% vs. 76%, p < .001). The most common complications were non-driveline infections (excluding sepsis) (44%), driveline infection (27%), need for continuous renal replacement therapy (25%) and right heart failure (24%). In a multivariate model age and left ventricular diastolic dimension was left as independent risk factors for mortality with a hazard ratio of 1.35 (95% confidence interval (CI) [1.01-1.80], p = .046) per 10 years and 0.88 (95% CI [0.72-0.99], p = .044) per 5 mm, respectively.

Conclusion: Outcome with CF LVAD in the Nordic countries was comparable to other cohorts. Higher age and destination therapy require particularly stringent selection.
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http://dx.doi.org/10.1080/14017431.2019.1583365DOI Listing
February 2019

Degree of differentiation of cutaneous squamous cell carcinoma: a comparison between a Swedish cohort of organ transplant recipients and immunocompetent patients.

Dermatol Pract Concept 2018 Oct 31;8(4):330-336. Epub 2018 Oct 31.

Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Organ transplant recipients (OTRs) have a very high risk of developing cutaneous squamous cell carcinoma (cSCC). Immunosuppressed OTRs may have a higher proportion of poorly differentiated cSCC than non-OTRs.

Objectives: The aim of this study was to investigate the degree of differentiation of cSCCs in OTRs compared with immunocompetent individuals.

Patients/methods: Data from the Swedish Cancer Registry were crosschecked with data from the Transplant registry of the Transplant Institute at Sahlgrenska University Hospital in Gothenburg, Sweden. All OTRs with a diagnosis of cSCC, basosquamous carcinoma, and/or cSCC in situ established at the Department of Dermatology, Sahlgrenska University Hospital, during 2002-2015 were included. The control group consisted of non-OTRs with the same diagnoses during the same time period.

Results: During 2002-2015, 82 OTRs diagnosed with 515 tumors and 883 non-OTRs with 1,247 tumors were included. OTRs developed 0.47 tumors/year vs 0.10 tumors/year for non-OTRs, but no significant differences were observed in the degree of tumor differentiation of invasive cSCCs between OTRs and non-OTRs (P = 0.4). The distribution of poorly, moderately, and well-differentiated invasive cSCCs among OTRs and non-OTRs were 8.5% vs 12.5%, 22.1% vs 29.9%, and 69.4% vs 57.6%, respectively.

Conclusions: OTRs do not develop a higher proportion of poorly differentiated cSCCs than non-OTRs.
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http://dx.doi.org/10.5826/dpc.0804a18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246062PMC
October 2018