Publications by authors named "Lars Gullestad"

319 Publications

Tocilizumab increases citrullinated histone 3 in non-ST segment elevation myocardial infarction.

Open Heart 2021 May;8(1)

Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.

Objective: Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties.

Methods: In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase-DNA (MPO-DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1-3).

Results: Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p<0.05), and H3Cit area under the curve (AUC) was 2.3 fold higher in the tocilizumab compared with placebo group (p<0.0001). (2) MPO-DNA and dsDNA did not differ between the groups. (3) In both treatment arms, dsDNA AUC was associated with TnT AUC. (4) Neutrophil count AUC correlated inversely to H3Cit AUC (p=0.015) in the total population.

Conclusions: In patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.
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http://dx.doi.org/10.1136/openhrt-2020-001492DOI Listing
May 2021

Prevalence of Iron Deficiency in Heart Transplant Recipients.

Clin Transplant 2021 May 10:e14346. Epub 2021 May 10.

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

Background: Optimal iron management is crucial to marginal patients such as heart transplant recipients. As inflammatory mechanisms are present in transplant recipients the definition of iron deficiency used in the general population might not be appropriate.

Objective: To evaluate the prevalence and determinants of iron deficiency in Norwegian heart transplant recipients.

Methods: We consecutively assessed iron parameters in all Norwegian heart transplant recipients at their annual follow-up. Several definitions of iron deficiency suggested in the literature were assessed: ferritin <100 µg/l, or ferritin 100-300 µg/l combined with transferrin saturation of <20 % (ID ); ferritin <100 µg/l (ID ); transferrin saturation of <20% (ID ), and ferritin <30 µg/l (ID ).

Results: 179 of 378 heart transplant recipients (47 %) had iron deficiency defined as ID . 152 patients (40%) had ID , and 103 patients (27%) had ID . 17 patients (5%) had ID . 88 patients (23%) had a C-reactive protein (CRP) >5.0 µg/l.

Conclusion: Iron deficiency defined as ID , ID or ID is prevalent in the heart transplant population, while ID is not. Further research is required to identify the mechanisms of iron homeostasis in heart transplant recipients, and to establish a definition of iron deficiency suitable for this population.
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http://dx.doi.org/10.1111/ctr.14346DOI Listing
May 2021

Effect of Continuous Positive Airway Pressure on Arrhythmia in Atrial Fibrillation and Sleep Apnea: A Randomized Controlled Trial.

Am J Respir Crit Care Med 2021 May 3. Epub 2021 May 3.

Oslo University Hospital, 155272, Oslo, Norway.

Rationale: Sleep apnea (SA) is highly prevalent in patients with atrial fibrillation (AF), and both conditions are associated with adverse cardiovascular outcomes.

Objectives: To determine the effect of continuous positive airway pressure (CPAP) on AF burden.

Methods: This open-label, parallel-group, randomized, controlled trial included patients with paroxysmal AF and moderate-to-severe SA (apnea-hypopnea index ≥15). Eligible patients were randomized (1:1) to 5 months' treatment with CPAP plus usual care (CPAP, n=55) or usual care alone (control, n=54) by a computerised system. Outcome assessment was blinded. The planned primary outcome was the difference between CPAP treatment and control in change of AF burden (% of time in AF), as measured by implantable loop recorder.

Measurements And Main Results: A total of 579 patients with paroxysmal AF had respiratory polygraphy, of whom 244 (42.1%) had moderate-to-severe SA. Of these, 158 (64.8%) participated in the CPAP run-in period, of whom 40 (25.3%) patients did not tolerate the treatment. One-hundred-eight patients were available for the primary analysis. The mean time in AF decreased from 5.6% at baseline to 4.1% during the last three months of CPAP intervention and from 5.0% to 4.3% in the control group. The adjusted between-group difference at follow-up was -0.63 (95% confidence interval: -2.55 to 1.30) percentage points; P=0.52. Seven serious adverse events (13%) occurred in the CPAP group, and two (4%) occurred in the control group.

Conclusions: In patients with paroxysmal AF and SA, treatment with CPAP did not result in a statistically significant reduction in the burden of AF. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02727192.
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http://dx.doi.org/10.1164/rccm.202011-4133OCDOI Listing
May 2021

Symptoms of anxiety after heart transplantation and their association with mortality: A secondary analysis.

Clin Transplant 2021 Apr 21:e14323. Epub 2021 Apr 21.

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

Background: Few studies, with inconclusive results, have examined the association of anxiety with mortality after heart transplantation (HTx). We examined whether anxiety symptoms, measured several years after HTx, are associated with increased mortality during long-term follow-up.

Methods: Anxiety symptoms were measured with the anxiety subscale of the Symptom Checklist-90-R (SCL-90-R) in 142 HTx recipients at a mean of 5.7 years (SD: 3.9) after HTx. Anxiety symptoms' impact on mortality during follow-up for up to 18.6 years was examined with Cox proportional hazard models. We accounted for relevant sociodemographic and clinical variables, including depressive symptoms (measured by the depression subscale of the SCL-90-R), in the multivariate analyses. In additional analyses, we explored the combined effect of anxious and depressive symptomatology.

Results: Anxiety symptoms were not significantly associated with mortality (univariate analysis: HR (95% CI): 1.04 (0.75-1.45); p = .813). Exploration of the combined effect of anxious and depressive symptomatology on mortality rendered non-significant results. Depressive symptoms were independently associated with mortality (multivariate analysis: HR (95% CI): 1.86 (1.07-3.24); p = .028).

Conclusions: Depressive symptoms' negative impact on survival after HTx was confirmed, while anxiety symptoms were not significantly associated with mortality during long-term follow-up. Anxiety symptoms' predictive role after HTx requires further study.
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http://dx.doi.org/10.1111/ctr.14323DOI Listing
April 2021

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

J Am Coll Cardiol 2021 Apr;77(15):1845-1855

Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response.

Objectives: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI.

Methods: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days.

Results: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups.

Conclusions: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).
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http://dx.doi.org/10.1016/j.jacc.2021.02.049DOI Listing
April 2021

Circulating regulators of the wingless pathway in precapillary pulmonary hypertension.

Respirology 2021 Apr 8. Epub 2021 Apr 8.

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

Background And Objective: Dysregulated Wnt signalling has been implicated in pulmonary hypertension (PH). We hypothesized that plasma levels of secreted Wnt proteins would be increased in patients with precapillary PH, correlate with indices of vascular resistance and cardiac function and give information on long-term prognosis.

Methods: We measured the Wnt ligand Wnt5a and secreted Wnt antagonists Dickkopf (DKK) DKK1, DKK3, secreted frizzled-related protein 3 (sFRP3), Wnt inhibitory factor-1 (WIF1) and sclerostin (SOST) in 106 patients with precapillary PH and 40 healthy controls. A second sample was obtained after a median of 4 months (n = 52). During a median of 90 months follow-up, 67 patients died.

Results: Our main findings were (i) Precapillary PH is characterized by enhanced systemic Wnt activity as reflected by elevated plasma levels of Wnt5a and secreted antagonists irrespective of diagnostic subgroups. (ii) WIF1 and in particular Wnt5a correlated with pulmonary vascular resistance and cardiac dysfunction. (iii) High levels of Wnt5a, sFRP3, DKK3 and WIF1 were associated with poor prognosis in age- and sex-adjusted analysis (hazard ratios per log/SD change ~1.4) and for DKK3 after further adjustment with right arterial pressure, pulmonary oxygen saturation, cardiac index, N-terminal pro B-type natriuretic peptide and peak oxygen uptake (VO ). Finally, an elevation of Wnt5a and DKK3 during follow-up was independently associated with poor prognosis.

Conclusion: Our data indicate that Wnt signalling pathways could be implicated in the pathogenesis of precapillary PH, and that some of the Wnt-related molecules (i.e., Wnt5a and DKK3) should be further investigated in these patients.
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http://dx.doi.org/10.1111/resp.14048DOI Listing
April 2021

Outcomes in asymptomatic, severe aortic stenosis.

PLoS One 2021 7;16(4):e0249610. Epub 2021 Apr 7.

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

Background And Aim Of The Study: Patients with asymptomatic, severe aortic stenosis are presumed to have a benign prognosis. In this retrospective cohort study, we examined the natural history of contemporary patients advised against aortic valve replacement due to a perceived lack of symptoms.

Materials And Methods: We reviewed the medical records of every patient given the ICD-10-code for aortic stenosis (I35.0) at Oslo University Hospital, Rikshospitalet, between Dec 1st, 2002 and Dec 31st, 2016. Patients who were evaluated by the heart team due to severe aortic stenosis were categorized by treatment strategy. We recorded baseline data, adverse events and survival for the patients characterized as asymptomatic and for 100 age and gender matched patients scheduled for aortic valve replacement.

Results: Of 2341 patients who were evaluated for aortic valve replacement due to severe aortic stenosis, 114 patients received conservative treatment due to a lack of symptoms. Asymptomatic patients had higher mortality than patients who had aortic valve replacement, log-rank p<0.001 (mean follow-up time: 4.0 (SD: 2.5) years). Survival at 1, 2 and 3 years for the asymptomatic patients was 88%, 75% and 63%, compared with 92%, 83% and 78% in the matched patients scheduled for aortic valve replacement. 28 (25%) of the asymptomatic patients had aortic valve replacement during follow-up. Age, previous history of coronary artery disease and N-terminal pro B-type natriuretic peptide (NT-proBNP) were predictors of mortality and coronary artery disease and NT-proBNP were predictors of 3-year morbidity in asymptomatic patients.

Conclusions: In this retrospective study, asymptomatic patients with severe aortic stenosis who were advised against surgery had significantly higher mortality than patients who had aortic valve replacement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249610PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026050PMC
April 2021

Intravenous iron supplement for iron deficiency in cardiac transplant recipients (IronIC): A randomized clinical trial.

J Heart Lung Transplant 2021 May 23;40(5):359-367. Epub 2021 Jan 23.

Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway; K.G. Jebsen Cardiac Research Center and Center for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway.

Aims: Heart transplant recipients have reduced exercise capacity despite preserved graft function. The IronIC trial was designed to test the hypothesis that intravenous iron therapy would improve peak oxygen consumption in these patients.

Methods And Results: This randomized, placebo-controlled, double-blind trial was performed at our national center for heart transplantation. One hundred and 2 heart transplant recipients with a serum ferritin <100 µg/liter or 100 to 300 µg/liter, in combination with transferrin saturation of <20%, and hemoglobin level >100 g/liter were enrolled ≥1 year after transplantation. A cardiopulmonary exercise test was performed before administration of the study drug and at 6 months follow-up. The primary endpoint was peak oxygen consumption. Key secondary outcomes included iron status, handgrip strength, quality of life, and safety. Fifty-two patients were randomized to receive ferric derisomaltose 20 mg/kg, and 50 to placebo. The between-group difference in baseline-adjusted peak oxygen consumption was 0.3 ml/kg/min (95% confidence interval -0.9 to 1.4, p = 0.66). In patients with a baseline ferritin <30 µg/liter, peak oxygen consumption was significantly higher in the ferric derisomaltose arm. At 6 months, iron stores were restored in 86% of the patients receiving ferric derisomaltose vs 20% in patients receiving placebo (p < 0.001). Quality of life was significantly better in patients receiving ferric derisomaltose. Twenty-seven adverse events occurred in the intravenous iron group vs 30 in the placebo group (p = 0.39).

Conclusion: Intravenous iron treatment did not improve peak oxygen consumption in heart transplant recipients with ferritin <100 µg/liter or 100 to 300 µg/liter in combination with transferrin saturation <20%.

Trial Registration Number: http//www.clinicaltrials.gov identifier NCT03662789.
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http://dx.doi.org/10.1016/j.healun.2021.01.1390DOI Listing
May 2021

Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction.

J Am Coll Cardiol 2021 Feb;77(4):405-419

Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway.

Background: Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.

Objectives: This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.

Methods: T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca homeostasis was studied in rat models of these conditions.

Results: HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca homeostasis, although diastolic Ca removal was also reduced. In contrast, Ca transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca impairments, including reduced sarco/endoplasmic reticulum Ca-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.

Conclusions: Although t-tubule disruption and impaired cardiomyocyte Ca release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.
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http://dx.doi.org/10.1016/j.jacc.2020.11.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840890PMC
February 2021

Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation.

Eur J Appl Physiol 2021 Mar 3;121(3):915-927. Epub 2021 Jan 3.

Department of Pediatrics, West Virginia University, Morgantown, WV, USA.

Purpose: Heart transplantation (HTx) implies denervation of afferent neural connections. Reinnervation of low-pressure cardiopulmonary baroreceptors might impact the development and treatment of hypertension, but little is known of its occurrence. The present prospective study investigated possible afferent reinnervation of low-pressure cardiopulmonary baroreceptors during the first year after heart transplantation.

Methods: A total of 50 heart transplant recipients (HTxRs) were included and were evaluated 7-12 weeks after transplant surgery, with follow-up 6 and 12 months later. In addition, a reference group of 50 healthy control subjects was examined once. Continuous, non-invasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 20° head-up tilt, during Valsalva maneuver and during 1 min of 30% maximal voluntary handgrip. In addition, routine clinical data including invasive measurements were used in the analyses.

Results: During the first year after HTx, the heart rate (HR) response to 20° head-up tilt partly normalized, a negative relationship between resting mean right atrial pressure and HR tilt response developed, low-frequency variability of the RR interval and systolic blood pressure at supine rest increased, and the total peripheral resistance response to Valsalva maneuver became stronger.

Conclusion: Functional assessments suggest that afferent reinnervation of low-pressure cardiopulmonary receptors occurs during the first year after heart transplantation, partially restoring reflex-mediated responses to altered cardiac filling.
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http://dx.doi.org/10.1007/s00421-020-04586-0DOI Listing
March 2021

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

Eur Heart J 2021 Feb;42(6):700-710

Department of Cardiology (CVK), Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Föhrer Str. 15, 13353 Berlin, Germany.

Aims: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF).

Methods And Results: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported.

Conclusion: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.
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http://dx.doi.org/10.1093/eurheartj/ehaa943DOI Listing
February 2021

Early Signs of Sinoatrial Reinnervation in the Transplanted Heart.

Transplantation 2020 Dec 14. Epub 2020 Dec 14.

Faculty of Medicine, University of Oslo, Oslo, Norway.

Background: Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation.

Methods: Fifty HTx recipients were assessed at 2.5, 6 and 12 months after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were carried out at supine rest, 0.2 Hz controlled breathing, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise.

Results: In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 months.

Conclusions: Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 months after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 months. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations.
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http://dx.doi.org/10.1097/TP.0000000000003580DOI Listing
December 2020

Distinct patterns of soluble leukocyte activation markers are associated with etiology and outcomes in precapillary pulmonary hypertension.

Sci Rep 2020 10 29;10(1):18540. Epub 2020 Oct 29.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0027, Oslo, Norway.

Activation of inflammatory processes has been identified as a major driver of pulmonary vascular remodeling that contributes to the development of precapillary pulmonary hypertension (PH). We hypothesized that circulating markers of leukocyte activation, reflecting monocytes/macrophages (sCD163, sCD14), T-cells (sCD25) and neutrophils (myeloperoxidase [MPO], neutrophil gelatinase-associated lipocalin [NGAL]) activity, could give prognostic information in precapillary PH. Circulating markers of leucocyte activation, sCD163, sCD14, sCD25, MPO and NGAL were measured by enzyme immunoassays in plasma from patients with idiopathic PAH (IPAH; n = 30); patients with PAH related to associated conditions (APAH; n = 44) and patients with chronic thromboembolic PH (CTEPH) (n = 32), and compared with 23 healthy controls. Markers of leucocyte activation were elevated in precapillary PH with particularly high levels in APAH. The elevated levels of monocyte/macrophage marker sCD163 was independently associated with poor long-term prognosis in the group as a whole, and elevated levels of sCD25 was associated with poor prognosis in APAH, while elevated levels of sCD163 and NGAL was associated with poor prognosis in IPAH and CTEPH. Our data show leucocyte activation in precapillary PH with different profiles and impact on prognosis according to etiology. The association of sCD163 with poor outcome in fully adjusted model may be of particular interest.
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http://dx.doi.org/10.1038/s41598-020-75654-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596076PMC
October 2020

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

Circ Heart Fail 2020 10 23;13(10):e006643. Epub 2020 Sep 23.

Research Institute of Internal Medicine (F.A., A.A., A.E.M., T.L., S.H., B.H., A.V.F., L.-E.V., S.N., T.R., P.A., T.U.), Institute of Basic Medical Sciences, University of Oslo, Norway.

Background: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS.

Methods: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed.

Results: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, <0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], <0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice).

Conclusions: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006643DOI Listing
October 2020

Cholesterol crystals use complement to increase NLRP3 signaling pathways in coronary and carotid atherosclerosis.

EBioMedicine 2020 Oct 11;60:102985. Epub 2020 Sep 11.

Centre of Molecular Inflammation Research, and Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Olav Kyrres gate 17, Trondheim 7030, Norway; The Central Norway Regional Health Authority, St. Olavs Hospital HF, Norway. Electronic address:

Background: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease.

Methods: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling.

Findings: Transcripts of interleukin (IL)-1beta(β) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1β protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1β, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components.

Interpretation: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis.
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http://dx.doi.org/10.1016/j.ebiom.2020.102985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494683PMC
October 2020

High-intensity interval training and health-related quality of life in de novo heart transplant recipients - results from a randomized controlled trial.

Health Qual Life Outcomes 2020 Aug 17;18(1):283. Epub 2020 Aug 17.

Department of Cardiology, Oslo University Hospital Rikshospitalet, Rikshospitalet, , PO Box 4950 Nydalen, N-0424, Oslo, Norway.

Background: Studies on the effect of high-intensity interval training (HIT) compared with moderate intensity continuous training (MICT) on health-related quality of life (HRQoL) after heart transplantation (HTx) is scarce. No available studies among de novo HTx recipients exists. This study aimed to investigate the effect of HIT vs. MICT on HRQoL in de novo recipients.

Methods: The HITTS study randomized eighty-one de novo HTx recipients to receive either HIT or MICT (1:1). The HIT intervention were performed with 2-4 interval bouts with an intensity of 85-95% of maximal effort. The MICT group exercised at an intensity of 60-80% of their maximal effort with a duration of 25 min. HRQoL was assessed by the Short Form-36 version 2 (SF-36v2) and the Hospital Anxiety and Depression Scale, mean 11 weeks after surgery and after a nine months' intervention. The participants recorded their subjective effect of the interventions on their general health and well-being on a numeric visual analogue scale. Clinical examinations and physical tests were performed. Differences between groups were investigated with independent Student t-tests and with Mann-Whitney U tests where appropriate. Within-group differences were analyzed with Paired-Sample t-tests and Wilcoxon Signed Rank tests. Correlations between SF-36 scores and VO were examined with Pearson's correlations.

Results: Seventy-eight participants completed the intervention. Both exercise modes were associated with improved exercise capacity on the physical function scores of HRQoL. Mental health scores remained unchanged. No differences in the change in HRQoL between the groups occurred except for Role Emotional subscale with a larger increase in the HIT arm. Better self-reported physical function was associated with higher VO and muscle strength.

Conclusion: HIT and MICT resulted in similar mean changes in HRQoL the first year after HTx. Both groups experienced significant improvements in the physical SF-36v2.

Trial Registration: ClinicalTrials.gov number: NCT01796379 Registered 18 February 2013.
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http://dx.doi.org/10.1186/s12955-020-01536-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433122PMC
August 2020

β-Blocker Doses and Heart Rate in Patients with Heart Failure: Results from the National Norwegian Heart Failure Registry.

Biomed Hub 2020 Jan-Apr;5(1):9-18. Epub 2020 Feb 21.

Department of Medicine and Healthcare, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.

Background: Use of β-blockers and titration to the highest tolerated dose are highly recommended by the European Society of Cardiology (ESC) guidelines for treatment of chronic heart failure (HF) with a reduced ejection fraction (HFrEF), but little attention has been paid to the achieved heart rate (HR) during this treatment.

Objectives: The aim of the present study was to examine the achieved HR in relation to the use of β-blockers in these patients.

Methods: All of the patients ( = 2,689) in the National Norwegian Heart Failure Registry as part of the Norwegian Cardiovascular Disease Registry with a sinus rhythm and left ventricular ejection fraction (LVEF) <40% at stable follow-up visiting specialised hospital outpatient HF clinics in Norway were included. The β-blocker doses were calculated as a percent of the target dose according to ESC HF guidelines. Differences between baseline variables according to the achieved HR were analysed by the Student's test for continuous variables and Pearson's χ test for categorical variables. Linear regression was used to determine the predictors of HR ≥70 beats/min (bpm) in the multivariate analysis.

Results: One third of the patients had a resting HR ≥70 bpm. Of the patients with an HR ≥70 bpm, 72.3% used less than the target dose of β-blocker; they were younger and had a higher NYHA class, more diabetes mellitus and chronic obstructive pulmonary disease (COPD), and higher N-terminal pro-B type natriuretic peptide (NT-proBNP) levels and estimated glomerular filtration rates compared to the patients with an HR <70 bpm. The 1-year mortality was 3.1, 3.7, 5.8, and 9.1% among the patients with an HR <70, 70-79, 80-89, and >89 bpm, respectively. Only 2 patients used ivabradine.

Conclusions: In patients with HFrEF and sinus rhythm, an HR ≥70 bpm was associated with worse clinical variables and outcomes. A high proportion of the patients who had an HR ≥70 bpm was not treated with or/did not tolerate the target dose of a β-blocker, although the β-blocker dose was higher than in patients with an HR <70 bpm. This may suggest that increased efforts should be made to further increase the β-blocker dose, and treatment with ivabradine could be considered among patients with an HR ≥70 bpm.
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http://dx.doi.org/10.1159/000505474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383246PMC
February 2020

Patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris randomised to an invasive versus conservative strategy: angiographic and procedural results from the After Eighty study.

Open Heart 2020 07;7(2)

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

Objectives: We aimed to report the angiographic and procedural results of the After Eighty study (ClinicalTrials.gov, NCT01255540), and to identify independent predictors of revascularisation.

Methods: Patients of ≥80 years old with non-ST-elevation myocardial infarction and unstable angina pectoris were randomised to an invasive or conservative strategy. Angiographic and procedural results were recorded. Univariate and multivariate analyses were performed to explore variables predicting revascularisation.

Results: Among 229 patients in the invasive group, 220 underwent immediate coronary angiography (90% performed via the radial artery). Of these patients, 48% had three-vessel disease or left main stenosis, 18% two-vessel disease, 16% one-vessel disease, 17% minor coronary vessel wall changes and two patients had normal coronary arteries. Six patients (3%) underwent coronary artery bypass graft. Percutaneous coronary intervention (PCI) was performed in 107 patients (49%), with 57% treated with bare metal stents, 37% drug-eluting stents and 6% balloon angioplasty. On average, 1.7 lesions were treated and 2 stents delivered per patient. Complications included 1 major PCI-related bleeding (successfully treated), 2 minor access site-related bleedings, 3 side branch occlusions during PCI and 11 periprocedural myocardial infarctions (considered end points). Sex, bundle branch block and smoking were independent predictors of revascularisation.

Conclusions: PCI was performed in approximately half of the patients, similar to findings in younger populations. Procedural success was high, with few complications.

Trial Registration Number: NCT01255540.
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http://dx.doi.org/10.1136/openhrt-2020-001256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380709PMC
July 2020

6 min walk test is a strong independent predictor of death in outpatients with heart failure.

ESC Heart Fail 2020 10 17;7(5):2904-2911. Epub 2020 Jul 17.

Department of Cardiology, Division of Cardiovascular and Pulmonary Diseases, Oslo University Hospital, Rikshospitalet, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Aims: The aim of this study was to examine the prognostic value of the 6 min walk test (6MWT) in a large cohort of outpatients with heart failure.

Methods And Results: A total of 5519 outpatients with heart failure from the National Norwegian Heart Failure Registry (NNHFR), which is part of the Norwegian Cardiovascular Disease Registry, were included in this analysis. The NNHFR recommended the use of the 6MWT for prognostic assessment of all patients included in the registry. Patients were categorized according to the 6MWT: Category 1 walked the longest and Category 3 the shortest. During a median (25th-75th percentiles) follow-up of 24 (14-36), 12.9% of the patients died. Patients in Category 3 had the overall worst outcome than had patients in Categories 1 and 2. 6MWT used as a continuous variable was a highly significant independent predictor for mortality in a multivariate Cox regression model adjusted for 16 other variables with a hazard ratio of 0.979 [(95% confidence interval 0.972-0.986), P < 0.001]. The four most important predictors for mortality were active cancer in the last 5 years, age, 6MWT, and natriuretic peptides (all P < 0.001).

Conclusions: 6MWT is a strong independent predictor of mortality in outpatients with HF. The findings support the use of the 6MWT in the prognostic assessment of patients with HF irrespective of HF aetiology.
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http://dx.doi.org/10.1002/ehf2.12900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524091PMC
October 2020

Effect of atorvastatin on muscle symptoms in coronary heart disease patients with self-perceived statin muscle side-effects: a randomized, double blinded crossover trial.

Eur Heart J Cardiovasc Pharmacother 2020 Jul 1. Epub 2020 Jul 1.

Department of Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Dronninggata 28, Drammen, Norway.

Aims: To estimate the effect of atorvastatin on muscle symptom intensity in coronary heart disease (CHD) patients with self-perceived statin-associated muscle symptoms (SAMS) and to determine the relationship to blood levels of atorvastatin and/or metabolites.

Methods And Results: A randomized multi-center trial consecutively identified 982 patients with previous or ongoing atorvastatin treatment after a CHD event. Of these, 97 (9.9%) reported SAMS and 77 were randomized to 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was the individual mean difference in muscle symptom intensity between the treatment periods, measured by visual-analogue scale (VAS) scores. Atorvastatin did not affect the intensity of muscle symptoms among 71 patients who completed the trial. Mean VAS difference [statin-placebo] was 0.31 (95% CI -0.24-0.86). The proportion with more muscle symptoms during placebo than atorvastatin was 17% (n = 12), 55% (n = 39) had the same muscle symptom intensity during both treatment periods whereas 28% (n = 20) had more symptoms during atorvastatin than placebo (confirmed SAMS). There were no differences in clinical or pharmacogenetic characteristics between these groups. The levels of atorvastatin and/or metabolites did not correlate to muscle symptom intensity among patients with confirmed SAMS (Spearmans rho ≤0.40, for all variables).

Conclusion: Re-challenge with high-intensity atorvastatin did not affect the intensity of muscle symptoms in CHD patients with self-perceived SAMS during previous atorvastatin therapy. There was no relationship between muscle symptoms and the systemic exposure to atorvastatin and/or its metabolites. The findings encourage an informed discussion to elucidate other causes of muscle complaints and continued statin use.
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http://dx.doi.org/10.1093/ehjcvp/pvaa076DOI Listing
July 2020

Effect of high-intensity interval training in young heart transplant recipients: results from two randomized controlled trials.

BMC Sports Sci Med Rehabil 2020 4;12:35. Epub 2020 Jun 4.

Department of Cardiology, Oslo University Hospital Rikshospitalet, postbox 4950, Nydalen, 0424 Oslo, Norway.

Background: Little is known about the effect of exercise in young heart transplant recipients, and results on group level is lacking. This study summarizes the findings of the youngest participants in two previous randomized controlled trials.

Method: This is a hypothesis-generating study reporting the main results from the youngest participants in two larger randomized controlled trials investigating the effect of high-intensity interval training (HIT). The article summarizes the main results from 28 young participants (< 40 year of age) who have participated in two previous studies which evaluated the effect of HIT vs. controls in adult heart transplant recipients. One of the studies included de novo heart transplant recipients and the other included maintenance heart transplant recipients.All study tests were performed in-hospital, in the specialist health care setting, but the exercise intervention was carried out locally, in cooperation with the primary health care. In both studies the exercise intervention lasted for 9-12 months. In one study, HIT (85-95% of peak effort) was compared to controls (no specific intervention), and in the other study HIT was compared to moderate, continuous exercise (MICT 60-80% of peak effort). The main outcome measure was peak oxygen uptake (VO) and a secondary endpoint was muscle strength.

Results: The summarized findings from the youngest heart transplant recipients in these two studies demonstrated mainly that the improvement in peak oxygen uptake among the younger recipients (< 40 years) was much larger (4.7 vs. 1.2 ml/kg/min and 7.0 vs. 2.2 ml/kg/min) compared to the improvement among the older recipients (≥ 40 years), and in accordance with results from adult heart transplant populations: HIT, compared to MICT, induced the largest improvement in peak oxygen consumption, also in the younger heart transplant recipients.

Conclusions: These results suggest that young heart transplant recipients have a greater effect of HIT than of MICT and may also suggest that younger recipients benefit more from high-intensity interval training than their older co-patients. However, larger randomized studies focusing on the young heart transplant population is strongly needed to confirm this hypothesis.

Trial Registration: Clinical trial registrations: NCT01796379 and NCT01091194.
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http://dx.doi.org/10.1186/s13102-020-00180-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271535PMC
June 2020

Novel Insights Into the Effects of Interleukin 6 Antagonism in Non-ST-Segment-Elevation Myocardial Infarction Employing the SOMAscan Proteomics Platform.

J Am Heart Assoc 2020 06 9;9(12):e015628. Epub 2020 Jun 9.

K.G. Jebsen Thrombosis Research and Expertise Center University of Tromsø Tromsø Norway.

Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non-ST-segment-elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C-reactive protein and troponin T were reduced in the active treatment arm. In this follow-up study, an aptamer-based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention-treated patients, 24 in the active intervention and 24 in the placebo-control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off-rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1-3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute-phase proteins lipopolysaccharide-binding protein, hepcidin, and insulin-like growth factor-binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C-C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMAscan aptamer-based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non-ST-segment-elevation myocardial infarction.
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http://dx.doi.org/10.1161/JAHA.119.015628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429051PMC
June 2020

Long-term effects of high-intensity training vs moderate intensity training in heart transplant recipients: A 3-year follow-up study of the randomized-controlled HITTS study.

Am J Transplant 2020 12 28;20(12):3538-3549. Epub 2020 Jun 28.

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

The randomized controlled High-Intensity Interval Training in De Novo Heart Transplant Recipients in Scandinavia (HITTS) study compared 9 months of high-intensity interval training (HIT) with moderate intensity continuous training in de novo heart transplant recipients. In our 3-year follow-up study, we aimed to determine whether the effect of early initiation of HIT on peak oxygen consumption (VO ) persisted for 2 years postintervention. The study's primary end point was the change in VO (mL/kg/min). The secondary end points were muscle strength, body composition, heart rate response, health-related quality of life, daily physical activity, biomarkers, and heart function. Of 78 patients who completed the 1-year HITTS trial, 65 entered our study and 62 completed the study tests. VO increased from baseline to 1 year and leveled off thereafter. During the intervention period, the increase in VO was larger in the HIT arm; however, 2 years later, there was no significant between-group difference in VO . However, the mean change in the anaerobic threshold and extensor muscle endurance remained significantly higher in the HIT group. Early initiation of HIT after heart transplantation appears to have some sustainable long-term effects. Clinical trial registration number: NCT01796379.
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http://dx.doi.org/10.1111/ajt.16087DOI Listing
December 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

Comparing manual and automatic scoring of sleep monitoring data from portable polygraphy.

J Sleep Res 2021 Apr 20;30(2):e13036. Epub 2020 May 20.

Department of Informatics, University of Oslo, Oslo, Norway.

We used sleep monitoring data from a study that investigated the prevalence, characteristics, risk factors and type of sleep apnea (SA) in 579 patients with paroxysmal atrial fibrillation. Most patients were screened for two nights, resulting in 1,043 sleep recordings that each contained data from one night. SA was diagnosed using the Nox T3 portable sleep monitor. An experienced sleep specialist scored the recordings manually using Noxturnal software. A total of 157 women (27%) and 422 men (73%) were examined; 477 (82.7%) had an apnea-hypopnea index (AHI) ≥ 5/hr, whereas moderate to severe SA (AHI ≥ 15/hr) was diagnosed in 243 patients (42.1%). The AHI derived from automatic and manual scoring showed a good agreement (Pearson's r coefficient of 0.96). The median difference in AHI was very small (i.e., 0.72 [mean difference, 1.06]), but was statistically significant (p < .0001). Automatic scoring classified sleep recordings with more than 90% accuracy into SA categories of mild (AHI ≥ 5/hr), moderate (AHI ≥ 15/hr) and severe (AHI ≥ 30/hr). We found a minor (11%-21%) mis-estimation of the number of recordings right above and below the boundary separating mild and moderate SA. The accuracy of automatic scoring differed from recording to recording, especially regarding the sensitivity of detecting disrupted breathing events. We found low to moderate agreement for the duration of disrupted breathing events (r = .53), for which the automatic scoring led to a statistically significant overestimation by 5.22 s (p < .0001).
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http://dx.doi.org/10.1111/jsr.13036DOI Listing
April 2021

Rosuvastatin alters the genetic composition of the human gut microbiome.

Sci Rep 2020 03 25;10(1):5397. Epub 2020 Mar 25.

Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

The gut microbiome contributes to the variation of blood lipid levels, and secondary bile acids are associated with the effect of statins. Yet, our knowledge of how statins, one of our most common drug groups, affect the human microbiome is scarce. We aimed to characterize the effect of rosuvastatin on gut microbiome composition and inferred genetic content in stool samples from a randomized controlled trial (n = 66). No taxa were significantly altered by rosuvastatin during the study. However, rosuvastatin-treated participants showed a reduction in the collective genetic potential to transport and metabolize precursors of the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO, p < 0.01), and an increase of related metabolites betaine and γ-butyrobetaine in plasma (p < 0.01). Exploratory analyses in the rosuvastatin group showed that participants with the least favorable treatment response (defined as < median change in high-density/low-density lipoprotein (HDL/LDL) ratio) showed a marked increase in TMAO-levels compared to those with a more favorable response (p < 0.05). Our data suggest that while rosuvastatin has a limited effect on gut microbiome composition, it could exert broader collective effects on the microbiome relevant to their function, providing a rationale for further studies of the influence of statins on the gut microbiome.
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http://dx.doi.org/10.1038/s41598-020-62261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096534PMC
March 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

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies.

J Hypertens 2020 07;38(7):1347-1354

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet.

Objective: Preeclampsia is a syndrome characterized by hypertension and poor placental development. The developmental wingless (Wnt) pathway plays an important role in placental development and we hypothesized that Wnt signaling would be dysregulated in preeclampsia.

Methods: To elucidate aberrations in the Wnt signaling pathway we conducted a pathway analysis on placental mRNA in late-onset preeclampsia and normal pregnancy from the STORK study [n = 10 in each group, RNA sequencing (RNAseq)] to identify differentially expressed genes. In addition, we compared circulating levels of secreted Wnt agonists and antagonists at term pregnancy and 6 months postpartum from an acute preeclampsia study (preeclampsia n = 34, normal pregnancy n = 61).

Results: We found circulating and placental mRNA levels of the secreted Wnt agonist R-spondin 3 (RSPO3) at term elevated in preeclampsia. Increased plasma RSPO3 was associated with high mean arterial pressure. Further, pathway analysis of placental tissue revealed elevated mRNA levels of upstream ligands WNT6 and WNT10A and frizzled receptors 2 and 4 in preeclampsia and downstream activation of the noncanonical Ca/NFAT pathway. Finally, plasma dickkopf 3 was decreased in preeclampsia 6 months postpartum.

Conclusion: We identify a potential role for RSPO3 and activation of noncanonical Wnt signaling in preeclampsia.
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http://dx.doi.org/10.1097/HJH.0000000000002362DOI Listing
July 2020