Lars Gullestad

• Broch, Kaspar; Andreassen, Arne K.; Anstensrud, Anne Kristine; Woxholt, Sindre; Flø, August Magnus Stensrød & Bjørkelund, Elisabeth [Vis alle 13 forfattere av denne artikkelen] (2026). Lipoprotein(a) in acute myocardial infarction – insights from the randomised ASSAIL-MI trial. Atherosclerosis. ISSN 0021-9150. 422. doi: 10.1016/j.atherosclerosis.2026.121903. Fulltekst i vitenarkiv
• Ueland, Thor; Dahl, Tuva Børresdatter; Michelsen, Annika Elisabet; Kleveland, Ola; Andersen, Geir Øystein & Anstensrud, Anne Kristine [Vis alle 13 forfattere av denne artikkelen] (2026). Effect of Interleukin-6 Receptor Inhibition by Tocilizumab on Platelet Activation and Markers of Thrombus Formation: A Substudy of the ASSAIL-MI Trial. Arteriosclerosis, Thrombosis and Vascular Biology. ISSN 1079-5642. doi: 10.1161/ATVBAHA.125.323587. Fulltekst i vitenarkiv
• Ueland, Thor; Andersen, Geir Øystein; Sharanga, Varathalingam; Khan, Yusuf; Holm, Sverre & Limalanathan, Shanmuganathan [Vis alle 12 forfattere av denne artikkelen] (2026). Circulating B-cell activating factor in acute coronary syndromes – association with adverse outcomes and progression of heart failure. Atherosclerosis. ISSN 0021-9150. 414. doi: 10.1016/j.atherosclerosis.2026.120642. Fulltekst i vitenarkiv
• Holt, Margrethe Flesvig; Michelsen, Annika Elisabet; Flø, August Magnus Stensrød; Russell, Kristoffer; Beitnes, Jan Otto & Kløve, Sophie Foss [Vis alle 12 forfattere av denne artikkelen] (2025). Increased dipeptidyl peptidase 4 in patients with concomitant transthyretin cardiac amyloidosis and severe aortic stenosis. International journal of cardiology: Heart and Vasculature (IJCHA). 61. doi: 10.1016/j.ijcha.2025.101820. Fulltekst i vitenarkiv Vis sammendrag

  Background Due to overlapping symptoms and signs, it can be challenging to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM) in the setting of concomitant aortic stenosis. Biomarkers may discriminate between heart failure with ATTR-CM and heart failure without ATTR-CM, but it is not known if these markers can differentiate between AS with and AS without concomitant ATTR-CM. Methods In 9 patients with ATTR-CM and AS, 161 patients with lone AS, and 23 healthy controls, we measured 8 plasma proteins previously identified by proteomic analysis as potential candidates for diagnosing ATTR-CM. We assessed differences between groups and association with indices of heart failure and AS severity. Results Plasma levels of dipeptidyl peptidase 4 (DPP4) were significantly higher in patients with AS and ATTR-CM than in patients with lone AS and in healthy controls. Lower levels of DPP4 were also associated with worse left ventricular function, higher New York Heart Association functional class, and low-flow, low-gradient aortic stenosis. Conclusions Our findings suggest that DPP4 may be a marker of ATTR-CM in patients with severe AS. In all AS patients, those with and without coexisting ATTR-CM, high DPP4 levels were asociated with better cardiac function.

• Dahl, Tuva Børresdatter; Jimenez, Ana Maria Teresa Quiles; Broch, Kaspar; Anstensrud, Anne Kristine; Gullestad, Lars & Andersen, Geir Øystein [Vis alle 16 forfattere av denne artikkelen] (2025). The N-6 methyladenosine dynamics in STEMI and the effect of IL-6 inhibition - a hypothesis generating sub-study of the ASSAIL-MI trial. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1532325. Fulltekst i vitenarkiv Vis sammendrag

  Background: Epitranscriptomics, with m6A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m6A RNA-regulation during myocardial infarction (MI). Methods: In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3–7 days, and from healthy control subjects (n=3). RNA was isolated, and m6A sites were analyzed using human m6A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis. Results: Compared with controls, patients with STEMI had a strikingly different pattern of m6A deposition. In total, 845 m6A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m6A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3–7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m6A deposition. Conclusions: In this hypothesis generating study, m6A deposition differs STEMI patients and healthy controls. The m6A pattern changes over the course of 3–7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.

• Ueland, Thor; Traaen, Gunn Marit; Hunt, Tove Elizabeth Frances; Aakerøy, Lars; Øverland, Britt & Bendz, Christina [Vis alle 14 forfattere av denne artikkelen] (2025). High levels of the adipokines leptin and metrnl in patients with paroxysmal atrial fibrillation and obstructive sleep apnea are not associated with the severity of sleep apnea or the burden of atrial fibrillation. Sleep Medicine. ISSN 1389-9457. 136. doi: 10.1016/j.sleep.2025.106862. Fulltekst i vitenarkiv
• Huse, Camilla; Murphy, Sarah Louise Mikalsen; Yang, Kuan; Balzer, Nora Reka; Stokke, Mathis Korseberg & Anstensrud, Anne Kristine [Vis alle 27 forfattere av denne artikkelen] (2025). The effects of interleukin-6-receptor inhibition on monocytes in STEMI: a substudy of the ASSAIL-MI trial. EBioMedicine. 121, s. 105960–105960. doi: 10.1016/j.ebiom.2025.105960. Fulltekst i vitenarkiv
• Bürker, Britta Susanne; Englund, Kristine Victoria Brautaset; Østby, Charlotte M.; Andersson, Stein; Gullestad, Lars & Broch, Kaspar (2025). Cognitive Function Among Heart Transplant Recipients Before and After Intravenous Iron Supplement for Iron Deficiency: Results From a Randomized, Placebo-Controlled, Double-Blind Treatment Trial. Clinical Transplantation. ISSN 0902-0063. 39(11). doi: 10.1111/ctr.70370. Fulltekst i vitenarkiv Vis sammendrag

  ABSTRACT Background Cognitive dysfunction after successful heart transplantation (HTx) is not uncommon. Lower hemoglobin levels have previously been associated with cognitive dysfunction in heart transplant recipients (HTx recipients). In a randomized, placebo‐controlled, double‐blind treatment trial, we assessed as a pre‐specified secondary outcome whether a single intravenous iron supplement for iron deficiency in HTx recipients resulted in changes in cognitive function after 6 months. Methods In the “Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients” (IronIC) trial, we assessed cognitive function at baseline and at 6‐month follow‐up with the following tests of the Cambridge Neuropsychological Test Automated Battery: Reaction Time, Paired Associates Learning, and Spatial Working Memory. Of 94 participants with cognitive data at baseline and follow‐up, 49 were randomized to the single intravenous iron supplement, while 45 received placebo. Results Raw score changes from baseline to follow‐up did not differ statistically significantly between study groups (two measures of each test analyzed). In the total sample, 27%–44% of participants performed at baseline at least one standard deviation below the normative mean on measures of memory and working memory/executive functions. Exploratory analyses indicated that performance on measures of memory might decrease more than expected with increasing age. Conclusion A single intravenous iron supplement for iron deficiency in HTx recipients did not result in statistically significant cognitive changes after 6 months. The group as a whole performed approximately half a standard deviation below the normative mean on measures of memory and working memory/executive functions. Regular cognitive screening after HTx is recommended. Clinical Trial Registration Trial Registration: ClinicalTrials.gov identifier: NCT03662789

• Hunt, Tove Elizabeth Frances; Traaen, Gunn Marit; Aakerøy, Lars; Øverland, Britt; Bendz, Christina & Michelsen, Annika Elisabet [Vis alle 15 forfattere av denne artikkelen] (2025). Systemic markers of inflammation and immune activation in patients with obstructive sleep apnea and paroxysmal atrial fibrillation. European journal of internal medicine. ISSN 0953-6205. 139. doi: 10.1016/j.ejim.2025.05.028. Fulltekst i vitenarkiv Vis sammendrag

  Background Atrial fibrillation (AF) and obstructive sleep apnea (OSA) frequently coexist, contributing to cardiovascular risk, possibly through shared inflammatory pathways. The specific role of inflammatory markers in patients with AF and OSA is not well established. Aim This study aimed to determine whether markers of inflammation and immune activation are elevated in patients with paroxysmal AF and OSA, assess the effects of continuous positive airway pressure (CPAP) and pulmonary vein isolation (PVI) on these markers, and evaluate their association with clinical outcomes, such as AF recurrence and thromboembolic risk. Methods We studied 143 patients with paroxysmal AF and moderate to severe OSA (apnea-hypopnea index ≥15). Of these, 99 were randomised to receive CPAP plus standard care (n = 51) or standard care alone (n = 48). A comparison group of 19 patients with paroxysmal AF and mild/no OSA (AHI <15) and 22 healthy controls were also included. Inflammatory markers related to leukocyte activation, vascular inflammation, and extracellular matrix remodelling were assessed at baseline, 6 months and 12 months follow-up. Results Patients with OSA and paroxysmal AF had higher levels of NGAL, PTX-3, GDF-15, MMP-9, VCAM1 and ANGP2 than healthy controls. These markers correlated poorly with AF and OSA severity. There was no modifying effect of CPAP on any marker. PTX3 was associated with AF recurrence and a high-risk score for thromboembolic stroke. Conclusion Moderate to severe OSA and AF are associated with elevated inflammatory markers. However, CPAP therapy did not significantly affect these levels. PTX-3 may hold prognostic value for AF recurrence and thromboembolic risk.

• Holt, Margrethe Flesvig; Michelsen, Annika Elisabet; Flø, August Magnus Stensrød; Khan, Yusuf; Bjørnø, Vilde & Skjelland, Mona [Vis alle 17 forfattere av denne artikkelen] (2025). Hepatocyte Growth Factor: A Marker of Cardiac Function, Mortality, and Disease Subtype in Cardiac Amyloidosis. JACC: Advances. 4(6). doi: 10.1016/j.jacadv.2025.101828. Fulltekst i vitenarkiv
• Berge, Kristian; Schirmer, Henrik; Øvrebotten, Tarjei; Nahoui, Hamza; Gullestad, Lars & Ingul, Charlotte Ingeborg Björk [Vis alle 13 forfattere av denne artikkelen] (2025). Improvements in medical therapy and prognosis for patients with HFrEF following the 2021 ESC HF guidelines. ESC Heart Failure. 12(5), s. 3343–3352. doi: 10.1002/ehf2.15337. Fulltekst i vitenarkiv Vis sammendrag

  Aims The guideline-directed medical therapy (GDMT) sequencing strategy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) underwent a paradigm shift with the 2021 ESC HF guidelines, from stepwise escalation to rapid simultaneous initiation of quadruple therapy. We aimed to assess the temporal trends in the use of GDMT and prognosis for patients with HFrEF. Methods and results Through the Norwegian HF Registry, we obtained data on patients treated at HF outpatient clinics with left ventricular ejection fraction ≤40% from 2016 through 2023 (n = 13 992), including GDMT, HF hospitalisations and mortality. Since 2016, >90% of patients have been treated with beta-blockers and renin-angiotensin-system-inhibitors, with angiotensin receptor-neprilysin inhibitors (ARNI) utilisation increasing from 4% in 2016 to 54% in 2023. Mineralocorticoid-receptor-antagonists (MRA) utilisation was at 36% in 2016, increased by 3% per year to 54% in 2021, and thereafter increased by 12% per year to 78% in 2023. Sodium-glucose cotransporter-2-inhibitors (SGLT2i) utilisation increased rapidly from 3% in 2020 to 85% in 2023. The utilisation of ≥50% of target dose followed similar trends. From 2016 to 2021, the crude 6-month mortality rate remained at 2.7%, followed by a decline of approximately 0.5% per year to 1.8% in 2023. HF hospitalisations declined steadily from 12.9% in 2016 to 8.2% in 2021, with a further decline to 6.8% in 2023. Conclusions The utilisation of GDMT in Norwegian HF clinics has increased markedly since 2016, with a fourfold acceleration in MRA and a substantial increase in SGLT2i use following the 2021 ESC HF guidelines. HF hospitalisations have consistently declined, while mortality rates first declined after 2021.

• Eriksson, Elin Svedlund; Rodriguez, Marta Lantero; Halvorsen, Bente; Johansson, Inger; Mårtensson, Anna K. F. & Wilhelmson, Anna S. [Vis alle 25 forfattere av denne artikkelen] (2025). Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow. Nature Communications. 16(1). doi: 10.1038/s41467-025-56217-x. Fulltekst i vitenarkiv
• Holt, Margrethe Flesvig; Flø, August Magnus Stensrød; Kaya, Esra; Kløve, Sophie Foss; Martinsen, Hege & Amlie, Kristine [Vis alle 16 forfattere av denne artikkelen] (2025). Transthyretin amyloid cardiomyopathy in aortic stenosis patients scheduled for transcatheter aortic valve implantation. ESC Heart Failure. 12(4), s. 2467–2476. doi: 10.1002/ehf2.15258. Fulltekst i vitenarkiv Vis sammendrag

  Aims The prevalences of aortic stenosis (AS) and transthyretin amyloid cardiomyopathy (ATTR-CM) increase with age. Identification of occult ATTR-CM in patients with AS can help explain out-of-proportion myocardial dysfunction, aid in prognostication and prompt initiation of disease-modifying treatment. Studies have suggested that many patients referred for transcatheter aortic valve implantation (TAVI) have concomitant ATTR-CM, but some have included unverified ATTR-CM in patients with ambiguous scintigrams. We aimed to assess the co-occurrence of ATTR-CM in patients scheduled for TAVI. Methods In patients accepted for TAVI for severe AS, we used bone scintigraphy to screen for ATTR-CM. We defined ATTR-CM as a cardiac tracer uptake ≥ Perugini Grade 2 in the absence of abnormal monoclonal protein or abnormal free light chain ratio. We offered bioptic verification to patients with Grade 1 or ambiguous DPD uptake. Results We included 171 consecutive patients aged 79 ± 7 years, 57% were male. Six patients (3.5%) had cardiac bone tracer uptake ≥ Perugini Grade 2 and no abnormal monoclonal protein/free light chains. Endomyocardial biopsies confirmed the diagnosis in two additional patients (1.2%), whereas five patients with low-grade uptake did not have ATTR-CM. In total, 8/171 patients (4.7%) were diagnosed with concomitant AS and ATTR-CM. Most of the patients with concomitant ATTR-CM had low-flow low-gradient (LFLG) AS, and 25% had a history of carpal tunnel syndrome. Conclusions We found concomitant AS and ATTR-CM in 5% of our TAVI patients. Carpal tunnel syndrome and LFLG AS suggest concomitant ATTR.

• Kindberg, Kristine Lovise Mørk; Broch, Kaspar; Andersen, Geir Øystein; Anstensrud, Anne Kristine; Åkra, Sissel & Woxholt, Sindre [Vis alle 23 forfattere av denne artikkelen] (2024). Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated With Infarct Size. JACC: Advances. 3(9). doi: 10.1016/j.jacadv.2024.101193. Fulltekst i vitenarkiv Vis sammendrag

  Background - Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect.<p> <p>Objectives - The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI.<p> <p>Methods - In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI).<p> <p>Results - All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P = 0.001 [dsDNA] and 0.02, P = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (β = 10.9 [95% CI: 4.0-15.0] [dsDNA] and β = 8.9 [95% CI: 2.0-15.9] [H3Cit], both P = 0.01).<p> <p>Conclusions - NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]

• Svenningsen, Alexander Robert; Søderstrøm, Sylvia; Sandbakk, Silvana Bucher; Gullestad, Lars; Bønaa, Kaare Harald & Wisløff, Ulrik [Vis alle 7 forfattere av denne artikkelen] (2024). Mind the intention-behavior gap: a qualitative study of post-myocardial infarction patients’ beliefs and experiences with long-term supervised and self-monitored physical exercise. BMC sports science, medicine and rehabilitation. 16(1). doi: 10.1186/s13102-024-00987-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Many post-myocardial infarction (MI) patients struggle with physical activity behavior change (BC) for life-long secondary prevention. There is limited knowledge about factors influencing long-term physical activity BC among post-MI patients. This qualitative study aimed to explore the beliefs and experiences related to post-MI patients’ physical activity BC process following a year’s participation in a supervised and self-monitored exercise program: the Norwegian Trial of Physical Exercise After MI (NorEx). Methods We conducted a qualitative study, performing in-depth semi-structured interviews with a randomly selected sample of NorEx participants when they were scheduled for cardiopulmonary exercise testing after one year of participation. Interviews were transcribed verbatim and the data was analyzed by applying reflexive thematic analysis. Results Seventeen participants (n = 4 female [24%]; median age, 61 years; median time since index MI, 4 years) were recruited and interviewed once. Analysis resulted in four main themes (nine sub-themes): (1) Personal responsibility to exercise (Exercise is safe, Health benefits, Habitual exercise); (2) Peer social support for a sense of safety and belonging (Social exercise, Supervision is preferred); (3) Research participation transformed exercise beliefs (High-intensity exercise is superior, Personal Activity Intelligence (PAI) promotes exercise adherence); and (4) Mind the intention-behavior gap (Initial anxiety, Lack of continued follow-up). Conclusions Several participants reported that they were able to maintain exercise BC during a year’s participation in NorEx. Nevertheless, a perceived lack of continued and individualized follow-up made some participants struggle with motivation and self-regulation, leading to an intention-behavior gap. Therefore, our findings suggest there is a need for individualized and continued social support and supervision from health and exercise professionals to maintain long-term exercise BC for secondary prevention among post-MI patients. Trial registration The NorEx study has been registered at ClinicalTrials.gov (NCT04617639, registration date 2020-10-21).

• Grov, Ingelin; Relbo, Anne; Arora, Satish; Bergh, Niklas; Rolid, Katrine & Gustafsson, Finn [Vis alle 13 forfattere av denne artikkelen] (2024). The Effect of Everolimus Versus Calcineurin Inhibitors on Quality of Life 10–12 Years After Heart Transplantation: The Results of a Randomized Controlled Trial (SCHEDULE Trial). Clinical Transplantation. ISSN 0902-0063. 38(11). doi: 10.1111/ctr.70028. Fulltekst i vitenarkiv Vis sammendrag

  Background Calcineurin inhibitors (CNIs) are associated with long-term complications after heart transplantation (HTx). Everolimus (EVR)-based immunosuppression allows for CNI withdrawal. We used data from The Scandinavian heart transplant everolimus de novo study with early CNI avoidance (SCHEDULE) trial to assess whether health-related quality of life (HRQoL) differed between patients on long-term treatment with EVR versus a CNI-based regimen. Methods In SCHEDULE, we randomized 115 patients (mean age 51 ± 13 years, 27% women) to cyclosporine (CNI group; n = 59), or early introduction of EVR and cyclosporine withdrawal within 11 weeks of HTx (EVR group; n = 56). The primary endpoint was the glomerular filtration rate. We used the Short Form-36 (SF-36v2), the EuroQoL visual analogue scale (EQ VAS), and the Beck Depression Inventory (BDI) to assess HRQoL. We re-evaluated the participants after 10–12 years. Results Seventy-eight patients attended follow-up at a median of 11 years after HTx. The SF-36 physical component summary score increased from 32 ± 10 pre-HTx to 44 ± 12 11 years after HTx (p < 0.01) in the EVR group and from 33 ± 9 to 44 ± 11 (p < 0.01) with CNI. The mental component summary score increased from 46 ± 12 to 53 ± 13 (EVR); p = 0.04 and from 38 ± 13 to 49 ± 13 (CNI); p < 0.01. Similar improvements were observed regarding EQ-VAS and the BDI. There were no significant between-group differences for either measure of HRQoL. Conclusions In heart transplant recipients, an EVR-based immunosuppressive strategy resulted in similar long-term improvements in HRQoL as treatment with a CNI-based regimen.

• Ribic, Darijan; Remme, Espen; Smiseth, Otto Armin; Massey, Richard; Eek, Christian & Kvitting, John-Peder [Vis alle 9 forfattere av denne artikkelen] (2024). Non-invasive myocardial work in aortic stenosis: Validation and improvement in left ventricular pressure estimation. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 25(2), s. 201–212. doi: 10.1093/ehjci/jead227. Fulltekst i vitenarkiv Vis sammendrag

  Aims The non-invasive myocardial work index (MWI) has been validated in patients without aortic stenosis (AS). A thorough assessment of methodological limitations is warranted before this index can be applied to patients with AS. Methods and results We simultaneously measured left ventricular pressure (LVP) by using a micromanometer-tipped catheter and obtained echocardiograms in 20 patients with severe AS. We estimated LVP curves and calculated pressure–strain loops using three different models: (i) the model validated in patients without AS; (ii) the same model, but with pressure at the aortic valve opening (AVO) adjusted to diastolic cuff pressure; and (iii) a new model based on the invasive measurements from patients with AS. Valvular events were determined by echocardiography. Peak LVP was estimated as the sum of the mean aortic transvalvular gradient and systolic cuff pressure. In same-beat comparisons between invasive and estimated LVP curves, Model 1 significantly overestimated early systolic pressure by 61 ± 5 mmHg at AVO compared with Models 2 and 3. However, the average correlation coefficients between estimated and invasive LVP traces were excellent for all models, and the overestimation had limited influence on MWI, with excellent correlation (r = 0.98, P < 0.001) and good agreement between the MWI calculated with estimated (all models) and invasive LVP. Conclusion This study confirms the validity of the non-invasive MWI in patients with AS. The accuracy of estimated LVP curves improved when matching AVO to the diastolic pressure in the original model, mirroring that of the AS-specific model. This may sequentially enhance the accuracy of regional MWI assessment.

• Holme, Fredric André; Huse, Camilla; Kong, Xiang Yi; Broch, Kaspar; Gullestad, Lars & Anstensrud, Anne Kristine [Vis alle 15 forfattere av denne artikkelen] (2024). Circular RNA Profile in Atherosclerotic Disease: Regulation during ST-Elevated Myocardial Infarction. International Journal of Molecular Sciences. ISSN 1661-6596. 25(16), s. 1–15. doi: 10.3390/ijms25169014. Fulltekst i vitenarkiv Vis sammendrag

  Circular (circ) RNAs are non-coding RNAs with important functions in the nervous system, cardiovascular system, and cancer. Their role in atherosclerosis and myocardial infarction (MI) remains poorly described. We aim to investigate the potential circRNAs in immune cells during atherogenesis and examine the most regulated during MI and the modulation by interleukin (IL)-6 receptor inhibition by tocilizumab. Wild-type (WT) and ApoE−/− mice were fed an atherogenic diet for 10 weeks, and the circRNA profile was analyzed by circRNA microarray. Whole blood from patients with ST-elevated MI (STEMI) and randomized to tocilizumab (n = 21) or placebo (n = 19) was collected at admission, 3–7 days, and at 6 months, in addition to samples from healthy controls (n = 13). Primers for human circRNA were designed, and circRNA levels were measured using RT-qPCR. mRNA regulation of predicted circRNA targets was investigated by RNA sequencing. The expression of 867 circRNAs differed between atherogenic and WT mice. In STEMI patients, circUBAC2 was significantly lower than in healthy controls. CircANKRD42 and circUBAC2 levels were inversely correlated with troponin T, and for circUBAC2, an inverse correlation was also seen with final infarct size at 6 months. The predicted mRNA targets for circUBAC2 and circANKRD42 were investigated and altered levels of transcripts involved in the regulation of inflammatory/immune cells, apoptosis, and mitochondrial function were found. Finally, tocilizumab induced an up-regulation of circANKRD42 and circUBAC2 3–7 days after percutaneous coronary intervention. CircRNA levels were dysregulated in STEMI, potentially influencing the immune system, apoptosis, and mitochondrial function.

• Broch, Kaspar; Lemström, Karl B.; Gustafsson, Finn; Eiskjær, Hans; Karason, Kristjan & Gjesdal, Grunde [Vis alle 17 forfattere av denne artikkelen] (2024). Randomized Trial of Cholesterol Lowering With Evolocumab for Cardiac Allograft Vasculopathy in Heart Transplant Recipients. JACC. Heart failure. ISSN 2213-1779. 12(10), s. 1677–1688. doi: 10.1016/j.jchf.2024.04.026. Fulltekst i vitenarkiv Vis sammendrag

  Background Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin–kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety. Objectives This double blind, randomized trial was conducted to test whether evolocumab reduces the burden of cardiac allograft vasculopathy. Methods Patients who had received a cardiac allograft at 1 of the Nordic transplant centers within the prior 4 to 8 weeks were randomized to monthly subcutaneous injections of evolocumab 420 mg or matching placebo. The primary endpoint was the baseline-adjusted maximal intimal thickness as measured by intracoronary ultrasound after 12 months’ treatment. Results The trial enrolled 128 patients between June 2019 and May 2022. Matched pairs of coronary ultrasound images were available for 56 patients assigned to evolocumab and 54 patients assigned to placebo. At 12 months, the adjusted mean difference in the maximal intimal thickness between the 2 arms was 0.017 mm (95% CI: −0.006 to 0.040; P = 0.14). The mean reduction in low-density lipoprotein cholesterol with evolocumab compared with placebo was 1.11 mmol/L (95% CI: 0.86-1.37 mmol/L). The use of evolocumab was not associated with an increase in adverse events. Conclusions Twelve months of treatment with evolocumab substantially reduced low-density lipoprotein cholesterol but did not reduce maximal coronary intimal thickness in HTx recipients. (Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients [EVOLVD]; NCT03734211)

• Bollano, Entela; Andreassen, Arne K.; Eiskjaer, Hans; Gustafsson, Finn; Rådegran, Göran & Gude, Einar [Vis alle 12 forfattere av denne artikkelen] (2024). Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. s. 1948–1959. doi: 10.1016/j.healun.2024.07.002. Fulltekst i vitenarkiv Vis sammendrag

  Background Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. Methods In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7–11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10–12-year long-term follow-up of the study. Results A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10–12 years visit was 82.7 (74.2–91.1) ml/min/1.73 m2 and 61.0 (52.3–69.7) ml/min/1.73 m2 in the everolimus and CNI group, respectively (p < 0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29–1.30) p = 0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57–1.77) p = 0.99). Conclusions De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10–12 years was similar in both groups and there was no difference in survival.

• Ruud, Marianne; Frisk, Michael; Melleby, Arne Olav; Norseng, Per Andreas; Mohamed, Belal A. & Li, Jia [Vis alle 22 forfattere av denne artikkelen] (2024). Regulation of cardiomyocyte t-tubule structure by preload and afterload: Roles in cardiac compensation and decompensation. Journal of Physiology. ISSN 0022-3751. 602(18), s. 4487–4510. doi: 10.1113/JP284566. Fulltekst i vitenarkiv Vis sammendrag

  Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca2+ homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles. Both preload and afterload increases produced a biphasic response, with the highest t-tubule densities observed at moderate loads, whereas excessively low and high loads resulted in low t-tubule levels. To determine the baseline position of the heart on this bell-shaped curve, mice were subjected to mildly elevated preload or afterload (1 week of aortic shunt or banding). Both interventions resulted in compensated cardiac function linked to increased t-tubule density, consistent with ascension up the rising limb of the curve. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation, aortic stenosis). T-tubule growth was associated with larger Ca2+ transients, linked to upregulation of L-type Ca2+ channels, Na+–Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients advanced the heart down the declining limb of the t-tubule–load relationship. This bell-shaped relationship was lost in the absence of electrical stimulation, indicating a key role of systolic stress in controlling t-tubule plasticity. In conclusion, modest augmentation of workload promotes compensatory increases in t-tubule density and Ca2+ cycling, whereas this adaptation is reversed in overloaded hearts during heart failure progression.

• Holt, Margrethe Flesvig; Holmen, Stine; Rolid, Katrine; Englund, Kristine Victoria Brautaset; Østby, Charlotte M. & Ravnestad, Håvard [Vis alle 10 forfattere av denne artikkelen] (2024). The association between body mass index, exercise capacity, and health-related quality of life in heart transplant recipients. Frontiers in Transplantation. 3. doi: 10.3389/frtra.2024.1379695. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Pre-transplant obesity and weight gain after heart transplantation are both associated with increased risk of poor clinical outcomes. We aimed to assess the association between overweight or obesity, exercise capacity, and health-related quality of life in heart transplant recipients. Methods: This study is based on baseline data from the IronIC trial, in which we randomized 102 heart transplant recipients with iron deficiency to ferric derisomaltose or placebo. We performed cardio pulmonary exercise testing in all participants. To assess quality of life, we used the SF-36v2 questionnaire, using two sum scores: the physical component summary and the mental component summary. A minimal clinically important difference was defined as ≥2 and ≥3 for the physical and the mental component summary, respectively. Results: 24/102 heart transplant recipients (24%) had a body mass index (BMI) ≥30 kg/m2. Peak oxygen consumption was 17.3 ± 4.6 ml/kg/min in the obese group vs. 24.7 ± 6.4 ml/kg/min in the group with a BMI <30 for a between-group difference of 7.4 (95% confidence interval 4.7–10.2) ml/kg/min: p < 0.001. The physical component summary score was on average 5.2 points lower in the patients with a body mass index ≥30 than in the lower weight group (p = 0.04). Conclusion: Almost a quarter of our heart transplant recipients in long-term follow-up had a BMI ≥30 kg/m2. These patients had substantially lower exercise capacity and lower quality of life in the physical domain.

• Myhre, Peder Langeland; Kleiven, Øyunn; Berge, Kristian; Grundtvig, Morten; Gullestad, Lars & Ørn, Stein (2024). Changes in 6-min walk test is an independent predictor of death in chronic heart failure with reduced ejection fraction. European Journal of Heart Failure. ISSN 1388-9842. 26(12), s. 2608–2615. doi: 10.1002/ejhf.3391. Fulltekst i vitenarkiv Vis sammendrag

  Aims Functional capacity provides important clinical information in patients with heart failure (HF) and reduced ejection fraction (HFrEF). The 6-min walk test (6MWT) is a simple and inexpensive tool for assessing functional capacity and risk. Although change in 6MWT is frequently used as a surrogate outcome in HF trials, the association with mortality is unclear. We aimed to assess the prognostic importance of changes in 6MWT. Methods and results Patients with chronic HFrEF referred to HF outpatient clinics in Norway completed a 6MWT at the first visit (baseline) and at a stable follow-up visit after treatment optimization (follow-up). Absolute and relative changes in 6MWT were analysed in association with mortality risk using Cox regression models and flexible cubic splines. The study included 3636 HFrEF patients aged 67.3 ± 11.6 years, 23% women, with left ventricular ejection fraction 30 ± 7%. At baseline, mean 6MWT was 438 ± 125 m, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1574 (732–3093) ng/L, and 27% had New York Heart Association (NYHA) class III/IV. After optimization of guideline-directed medical therapy (median 147 [86–240] days), 6MWT increased by mean 40 ± 74 m, NT-proBNP decreased by median 425 (14–1322) ng/L, and NYHA class improved in 38% of patients. Patients with greater improvements in 6MWT were younger, with greater improvements in NYHA class (r = 0.27, p < 0.001) and larger reductions in NT-proBNP concentrations (r = 0.19, p < 0.001). After mean 845 ± 595 days, 419 (11.5%) patients were dead. Both absolute and relative changes in 6MWT were non-linearly associated with survival, attenuating as 6MWT increased. A 50 m increase in 6MWT was associated with a 17% lower mortality risk (hazard ratio 0.84, 95% confidence interval 0.77–0.90, p < 0.001) in the fully adjusted model, including changes in NYHA class, NT-proBNP concentrations, and other established risk factors. The associations were more pronounced in patients with lower baseline 6MWT and higher age. Conclusion Improvement in 6MWT in patients with HFrEF is associated with increased survival, independent of changes in NT-proBNP and NYHA class. These findings support 6MWT change as a surrogate outcome in HF trials.

• Woxholt, Sindre; Ueland, Thor; Aukrust, Pål; Anstensrud, Anne Kristine; Broch, Kaspar & Tøllefsen, Ingvild Maria [Vis alle 15 forfattere av denne artikkelen] (2024). Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI. International Journal of Cardiology. ISSN 0167-5273. 418. doi: 10.1016/j.ijcard.2024.132613. Fulltekst i vitenarkiv Vis sammendrag

  Background: Tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size. Methods: This is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1–2, 3–7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months. Results: Tocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly. Conclusion: This study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines.

• Hunt, Tove Elizabeth Frances; Traaen, Gunn Marit; Aakerøy, Lars; Massey, Richard; Bendz, Christina & Øverland, Britt [Vis alle 17 forfattere av denne artikkelen] (2024). Cardiac remodelling in patients with atrial fibrillation and obstructive sleep apnoea. Open heart. 11(2). doi: 10.1136/openhrt-2024-002718. Fulltekst i vitenarkiv Vis sammendrag

  Background Obstructive sleep apnoea (OSA) can cause left atrial (LA) and left ventricular (LV) remodelling, which is linked to atrial fibrillation (AF). Whether continuous positive airway pressure (CPAP) can reverse LA and LV remodelling in patients with OSA and paroxysmal AF (PAF) has yet to be studied. We assessed the impact of CPAP treatment on LA and LV size and function in patients with OSA and PAF before and after catheter ablation. Methods In a randomised controlled trial, we screened patients with PAF for OSA. We enrolled patients with an Apnoea–Hypopnoea Index ≥15/hour. The burden of AF was monitored by an implantable loop recorder in all patients. Patients were then randomised to CPAP treatment or standard care. Transthoracic echocardiography was performed at baseline and after 6 and 12 months to assess LV and LA function and remodelling with advanced echocardiographic imaging techniques. Results We enrolled 109 patients (63±7 years, body mass index 29.6±4.3, 76% men). 83 patients were scheduled for pulmonary vein isolation (PVI) and 26 for clinical follow-up only. 55 patients were randomised to CPAP and 54 to standard care. The burden of AF decreased significantly in patients who underwent PVI irrespective of treatment with CPAP (p for difference ≤0.001). Patients in the study group had LV ejection fraction (LVEF) and LV global longitudinal strain (GLS) within the normal range, increased LA Volume Index (LAVI), LA volume (by speckle tracking) and decreased LA reservoir strain at baseline. We did not observe any improvement in LVEF, GLS, LAVI, LA volume or LA reservoir strain in either group during the 12 months of follow-up. Conclusions In patients with PAF and OSA, treatment with CPAP was not associated with reverse LA remodelling within 12 months of follow-up.

• Ravnestad, Håvard; Murbræch, Klaus; Gjønnæss, Eyvind; Andersen, Rune; Moe, Natasha & Birkeland, Sigurd [Vis alle 13 forfattere av denne artikkelen] (2024). Right ventricular remodelling and long-term survival after pulmonary endarterectomy versus balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Heart. ISSN 1355-6037. doi: 10.1136/heartjnl-2024-324243. Fulltekst i vitenarkiv
• Raju, Sajan; Molinaro, Antonio; Awoyemi, Ayodeji Olawale; Jørgensen, Silje Fjellgård; Braadland, Peder Rustøen & Nendl, Andraz [Vis alle 19 forfattere av denne artikkelen] (2024). Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity. Genome Medicine. 16(1), s. 27–27. doi: 10.1186/s13073-024-01296-6. Fulltekst i vitenarkiv Vis sammendrag

  <p><i>Background</i> Interactions between the gut microbiota, diet, and host metabolism contribute to the development of cardiovascular disease, but a firm link between disease-specific gut microbiota alterations and circulating metabolites is lacking. <p><i>Methods</i> We performed shot-gun sequencing on 235 samples from 166 HF patients and 69 healthy control samples. Separate plasma samples from healthy controls (n = 53) were used for the comparison of imidazole propionate (ImP) levels. Taxonomy and functional pathways for shotgun sequencing data was assigned using MetaPhlAn3 and HUMAnN3 pipelines. <p><i>Results</i> Here, we show that heart failure (HF) is associated with a specific compositional and functional shift of the gut microbiota that is linked to circulating levels of the microbial histidine-derived metabolite ImP. Circulating ImP levels are elevated in chronic HF patients compared to controls and associated with HF-related gut microbiota alterations. Contrary to the microbiota composition, ImP levels provide insight into etiology and severity of HF and also associate with markers of intestinal permeability and systemic inflammation. <p><i>Conclusions</i> Our findings establish a connection between changes in the gut microbiota, the presence, etiology, and severity of HF, and the gut-microbially produced metabolite ImP. While ImP appears promising as a circulating biomarker reflecting gut dysbiosis related to HF, further studies are essential to demonstrate its causal or contributing role in HF pathogenesis.

• Christensen, Anders Haugom; Wyller, Vegard Bruun Bratholm; Nygaard, Sissel; Rolid, Katrine; Nytrøen, Kari & Gullestad, Lars [Vis alle 10 forfattere av denne artikkelen] (2023). Factors Associated with Sinoatrial Reinnervation after Heart Transplantation. Transplantation direct. 9(12). doi: 10.1097/TXD.0000000000001553. Fulltekst i vitenarkiv Vis sammendrag

  Background. Factors associated with sympathetic and parasympathetic sinoatrial reinnervation after heart transplantation (HTx) are inadequately studied. Methods. Fifty transplant recipients were examined at 7 to 12 wk (index visit), 6, 12, 24, and 36 mo after HTx. Supine rest heart rate variability in the low-frequency (LF) domain (sympathetic and parasympathetic sinoatrial reinnervation) and the high-frequency (HF) domain (parasympathetic sinoatrial reinnervation) were measured repeatedly and related to selected recipient, donor, and perisurgical characteristics. We primarily aimed to identify index visit factors that affect the sinoatrial reinnervation process. Secondarily, we examined overall associations between indices of reinnervation and repeatedly measured recipient characteristics to generate new hypotheses regarding the consequences of reinnervation. Results. LF and HF variability increased time dependently. In multivariate modeling, a pretransplant diagnosis of nonischemic cardiomyopathy (P = 0.038) and higher index visit handgrip strength (P = 0.028) predicted improved LF variability. Recipient age, early episodes of rejection, and duration of extracorporeal circulation were not associated with indices of reinnervation. Study average handgrip strength was positively associated with LF and HF variability (respectively, P = 0.005 and P = 0.029), whereas study average C-reactive protein was negatively associated (respectively, P = 0.015 and P = 0.008). Conclusions. Indices of both sympathetic and parasympathetic sinoatrial reinnervation increased with time after HTx. A pretransplant diagnosis of nonischemic cardiomyopathy and higher index visit handgrip strength predicted higher indices of mainly sympathetic reinnervation, whereas age, rejection episodes, and duration of extracorporeal circulation had no association. HTx recipients with higher indices of reinnervation had higher average handgrip strength, suggesting a link between reinnervation and improved frailty. The more reinnervated participants had lower average C-reactive protein, suggesting an inhibitory effect of reinnervation on inflammation, possibly through enhanced function of the inflammatory reflex. These potential effects of reinnervation may affect long-term morbidity in HTx patients and should be scrutinized in future research.

• Woxholt, Sindre; Ueland, Thor; Aukrust, Pål; Anstensrud, Anne Kristine; Broch, Kaspar & Tøllefsen, Ingvild Maria [Vis alle 20 forfattere av denne artikkelen] (2023). Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab. Open heart. 10(2), s. 1–8. doi: 10.1136/openhrt-2023-002301. Fulltekst i vitenarkiv Vis sammendrag

  Background Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. Methods STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24–36, 72–168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. Results Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=−0.29, –0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=−0.09,–0.14, respectively). Conclusions Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients.

• Berg, Erlend; Tegn, Nicolai Kloumann; Abdelnoor, Michael; Røysland, Kjetil; Ryalen, Pål Christie & Aaberge, Lars [Vis alle 14 forfattere av denne artikkelen] (2023). Long-Term Outcomes of Invasive vs Conservative Strategies for Older Patients With Non–ST-Segment Elevation Acute Coronary Syndromes. Journal of the American College of Cardiology. ISSN 0735-1097. 82(21), s. 2021–2030. doi: 10.1016/j.jacc.2023.09.809. Fulltekst i vitenarkiv Vis sammendrag

  Background Non–ST-segment elevation acute coronary syndrome (NSTE-ACS) is a frequent cause of hospital admission in older people, but clinical trials targeting this population are scarce. Objectives The After Eighty Study assessed the effect of an invasive vs a conservative treatment strategy in a very old population with NSTE-ACS. Methods Between 2010 and 2014, the investigators randomized 457 patients with NSTE-ACS aged ≥80 years (mean age 85 years) to an invasive strategy involving early coronary angiography with immediate evaluation for revascularization and optimal medical therapy or to a conservative strategy (ie, optimal medical therapy). The primary endpoint was a composite of myocardial infarction, need for urgent revascularization, stroke, and death. The long-term outcomes are presented. Results After a median follow up of 5.3 years, the invasive strategy was superior to the conservative strategy in the reduction of the primary endpoint (incidence rate ratio: 0.76; 95% CI: 0.63-0.93; P = 0.0057). The invasive strategy demonstrated a significant gain in event-free survival of 276 days (95% CI: 151-400 days; P = 0.0001) at 5 years and 337 days (95% CI: 123-550 days; P = 0.0001) at 10 years. These results were consistent across subgroups of patients with respect to major cardiovascular prognostic factors. Conclusions In patients aged ≥80 years with NSTE-ACS, the invasive strategy was superior to the conservative strategy in the reduction of composite events and demonstrated a significant gain in event-free survival. (The After Eighty Study: a randomized controlled trial; NCT01255540)

• Berg, Randi; Clemmensen, Tor S.; Petersen, Mikkel S.; Mogensen, Lone J.H.; Christiansen, Mette & Rolid, Katrine [Vis alle 11 forfattere av denne artikkelen] (2023). Kinetics of Torque Teno virus in heart transplant patients. Human Immunology. ISSN 0198-8859. doi: 10.1016/j.humimm.2023.110720. Fulltekst i vitenarkiv Vis sammendrag

  End-stage heart failure often requires heart transplantation as a life-prolonging treatment. Immunosuppressive therapy is necessary to avoid rejection, but is associated with serious adverse effects. New approaches are needed to monitor immune function in heart transplant patients. We here report the kinetics of Torque Teno Virus (TTV) after transplantation in a large cohort of heart transplant patients and examine its possible role in predicting rejection. We included 106 patients from Aarhus University Hospital and Oslo University Hospital. Patients were followed for 3 years with clinical assessments, biopsies, TTV measurements, and flowcytometric phenotyping. We observed TTV levels reaching a maximum 3 months after transplantation for all 106 patients, after which levels gradually declined. 38 patients (38 %) had biopsy-proven rejection within the first year. We did not find evidence of an association between TTV and serum trough levels, events of rejection, nor flow cytometric immunophenotype. We report data on a large cohort of heart transplant patients and contribute to the understanding of how TTV behaves in transplant patients. Despite not finding an association with rejection, our results provide important insights into the kinetics of TTV levels after transplantation, which may be useful in future studies of immune function in heart transplant patients.

• Arora, Satish; Zimmermann, Frederik M.; Solberg, Ole Geir; Nytrøen, Kari; Aaberge, Lars & Okada, Kozo [Vis alle 13 forfattere av denne artikkelen] (2023). Prognostic value of intravascular ultrasound early after heart transplantation. European Heart Journal. ISSN 0195-668X. 44(48), s. 5160–5162. doi: 10.1093/eurheartj/ehad648. Fulltekst i vitenarkiv
• Dodgson, Christopher Alexander Steele; Beitnes, Jan Otto; Kløve, Sophie Foss; Herstad, Jon; Opdahl, Anders & Undseth, Ragnhild Marie [Vis alle 13 forfattere av denne artikkelen] (2023). An investigator-sponsored pragmatic randomized controlled trial of AntiCoagulation vs AcetylSalicylic Acid after Transcatheter Aortic Valve Implantation: Rationale and design of ACASA-TAVI. American Heart Journal. ISSN 0002-8703. 265, s. 225–232. doi: 10.1016/j.ahj.2023.08.010. Fulltekst i vitenarkiv Vis sammendrag

  Background The optimal antithrombotic therapy after transcatheter aortic valve implantation (TAVI) is unknown. Bioprosthetic valve dysfunction (BVD) is associated with adverse outcomes and may be prevented by anticoagulation therapy. A dedicated randomized trial comparing monotherapy NOAC to single antiplatelet therapy has not been performed previously. We hypothesize that therapy with any anti-factor Xa NOAC will reduce BVD compared to antiplatelet therapy, without compromising safety. Methods ACASA-TAVI is a multicenter, prospective, randomized, open-label, blinded endpoint, all-comers trial comparing a monotherapy anti-factor Xa NOAC strategy (intervention arm) with a single antiplatelet therapy strategy (control arm) after successful TAVI. Three-hundred and sixty patients without indication for oral anticoagulation will be randomized in a 1:1 ratio to either apixaban 5 mg twice per day, edoxaban 60 mg daily, or rivaroxaban 20 mg daily for 12 months followed by acetylsalicylic acid 75 mg daily indefinitely, or to acetylsalicylic acid 75 mg daily indefinitely. The 2 co-primary outcomes are (1) incidence of Hypo-Attenuated Leaflet Thickening (HALT) on 4-dimensional cardiac CT at 12 months, and (2) a Safety Composite of VARC-3 bleeding events, thromboembolic events (myocardial infarction and stroke), and death from any cause, at 12 months. Results The first 100 patients had a mean age of 74 ± 3.6 years, 33% were female, the average body-mass index was 27.9 ± 4.4 kg/m2, and 15% were smokers. A balloon-expanded valve was used in 82% and a self-expandable valve in 18%. Conclusions The trial is planned, initiated, funded, and conducted without industry involvement.

• Sverre, Elise Christine Bjørkholen; Munkhaugen, John; Kristiansen, Oscar; Weedon-Fekjær, Harald; Peersen, Kari & Gjertsen, Erik [Vis alle 10 forfattere av denne artikkelen] (2023). Plasma concentration of atorvastatin metabolites correlates with low-density lipoprotein cholesterol reduction in patients with coronary heart disease. Pharmacology Research & Perspectives. 11(3). doi: 10.1002/prp2.1089. Fulltekst i vitenarkiv Vis sammendrag

  In this exploratory study from a randomized double-blinded crossover trial including 70 patients with coronary heart disease and self-perceived muscular side effects of statins, we aimed to determine the relationship between low-density lipoprotein cholesterol (LDL-C) reduction and atorvastatin metabolite plasma concentrations. All patients underwent a 7 weeks treatment period with atorvastatin 40 mg/day and a 7 weeks placebo period in random order. Nonlinear regression with a three-parameter equation explored the relationship between percentage LDL-C reduction (statin vs. placebo) and the pharmacokinetic variables. Mean LDL-C reduction was 49% (range 12% to 71%). The sum of 4-OH-atorvastatin acid and lactone correlated moderately with the LDL-C response (Spearman ρ 0.27, 95% confidence interval [CI]: 0.03 to 0.48). Accordingly, nonlinear regression showed R2 of 0.14 (95% CI: 0.03 to 0.37, R2 adjusted equaled 0.11). Even a perfect underlying correlation of 1.0 showed R2 = 0.32 by simulation, using historical intra-individual LDL-C variation (8.5%). The 90% inhibitory concentration was 2.1 nmol/L, and the 4-OH-metabolite sum exceeded this threshold in 34% of the patients. In conclusion, trough plasma concentrations of 4-OH-atorvastatin metabolites correlated moderately to the LDL-C reduction. A plateau LDL-C response was observed above a pharmacokinetic threshold, below which the response was highly variable. The usefulness of monitoring concentrations of atorvastatin metabolites to optimize the individual dosage have limitations, but its supportive potential may be pursued in relevant patient subsets to achieve adequate efficacy at the lowest possible dose. The results add knowledge to the overall understanding of the variable LDL-C response mediated by atorvastatin.

• Rafique, Muzammil; Solberg, Ole Geir; Gullestad, Lars; Bendz, Bjørn; Murbræch, Klaus & Nytrøen, Kari [Vis alle 8 forfattere av denne artikkelen] (2023). Effects of high-intensity interval training on cardiac remodelling, function and coronary microcirculation in de novo heart transplant patients: a substudy of the HITTS randomised controlled trial. BMJ Open sport & exercise medicine. 9(3). doi: 10.1136/bmjsem-2022-001331. Fulltekst i vitenarkiv Vis sammendrag

  Objectives High-intensity interval training (HIT) improves peak oxygen consumption (VO2peak) in de novo heart transplant (HTx) recipients. It remains unclear whether this improvement early after HTx is solely dependent on peripheral adaptations, or due to a linked chain of central and peripheral adaptations. The objective of this study was to determine whether HIT results in structural and functional adaptations in the cardiovascular system. Methods Eighty-one de novo HTx recipients were randomly assigned to participate in either 9 months of supervised HIT or standard care exercise-based rehabilitation. Cardiac function was assessed by echocardiogram and the coronary microcirculation with the index of microcirculatory resistance (IMR) at baseline and 12 months after HTx. Results Cardiac function as assessed by global longitudinal strain was significantly better in the HIT group than in the standard care group (16.3±1.2% vs 15.6±2.2%, respectively, treatment effect = –1.1% (95% CI –2.0% to –0.2%), p=0.02), as was the end-diastolic volume (128.5±20.8 mL vs 123.4±15.5 mL, respectively, treatment effect=4.9 mL (95% CI 0.5 to 9.2 mL), p=0.03). There was a non-significant tendency for IMR to indicate improved microcirculatory function (13.8±8.0 vs 16.8±12.0, respectively, treatment effect = –4.3 (95% CI –9.1 to 0.6), p=0.08). Conclusion When initiated early after HTx, HIT leads to both structural and functional cardiovascular adaptations.

• Ravnestad, Håvard; Andersen, Rune; Birkeland, Sigurd; Svalebjørg, Morten; Lingaas, Per Snorre & Gude, Einar [Vis alle 10 forfattere av denne artikkelen] (2023). Pulmonary endarterectomy and balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: Comparison of changes in hemodynamics and functional capacity. Pulmonary Circulation (PC). ISSN 2045-8932. 13(1), s. 1–12. doi: 10.1002/pul2.12199. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). Balloon pulmonary angioplasty (BPA) is an emerging option for inoperable patients. Comparisons of the hemodynamic and functional outcome between these treatments are scarce. In this single‐center observational cohort study, we compared hemodynamics by right heart catheterization and peak oxygen consumption before and 5 months (±14 days) after either PEA or BPA. Comprehensive evaluation and selection for PEA or BPA was performed by an expert CTEPH team. Fourty‐two and fourty consecutive patients were treated with PEA or BPA, respectively. Demographics were similar between groups. Both PEA and BPA significantly reduced mean pulmonary artery pressure (from 46 ± 11 mmHg at baseline to 28 ± 13 mmHg at follow‐up; p  &lt; 0.001 and from 43 ± 12 mmHg to 31 ± 9 mmHg; p  &lt; 0.001) and pulmonary vascular resistance (from 686 ± 347 dyn s cm −5 at baseline to 281 ± 197 dyn s cm −5 at follow‐up; p  &lt; 0.001 and from 544 ± 322 dyn s cm −5 to 338 ± 180 dyn s cm −5 ; p  &lt; 0.001), with significantly lower reductions for both parameters in the former group. However, cardiopulmonary exercise testing revealed no significant between group differences in exercise capacity. Diffusion capacity for carbon monoxide at baseline was the only follow‐up predictor for peak VO 2 . In our study, PEA reduced pulmonary pressures more than BPA did, but similar improvements were observed for exercise capacity. Thus, while long term data after BPA is lacking, BPA treated CTEPH patients can expect physical gains in line with PEA.

• Holt, Margrethe Flesvig; Flø, August Magnus Stensrød; Ravnestad, Håvard; Bjørnø, Vilde; Gullestad, Lars & Andreassen, Arne K. [Vis alle 8 forfattere av denne artikkelen] (2023). Invasive haemodynamics at rest and exercise in cardiac amyloidosis. ESC Heart Failure. doi: 10.1002/ehf2.14621. Fulltekst i vitenarkiv Vis sammendrag

  Aims Our aim was to investigate haemodynamics at rest and during exercise in patients with transthyretin cardiomyopathy (ATTR-CM) in light of the 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines on pulmonary hypertension (PH). Methods and results We performed right heart catheterization (RHC) in 57 subjects with ATTR-CM. The proportion of patients with PH was 77% according to the 2022 guidelines versus 47% when applying the 2015 guidelines. Isolated post-capillary PH and combined pre- and post-capillary PH were most prevalent. Thirty-six patients underwent a supine bicycle cardiopulmonary exercise test during RHC. Exercise-induced PH was defined as an increase in mean pulmonary arterial pressure from rest to exercise per increase in cardiac output (ΔmPAP/ΔCO) of > 3 mmHg/L/min. An increase in pulmonary arterial wedge pressure per change in cardiac output (ΔPAWP/ΔCO) from rest to exercise >2 mmHg/L/min was considered suggestive of post-capillary exercise-induced PH. All but two patients who exercised during RHC developed exercise-induced PH. The median ΔmPAP/ΔCO was 7.2 mmHg/L/min and ΔPAWP/ΔCO was 5.1 mmHg/L/min. The median ΔRAP/ΔCO was 3.6 mmHg/L/min and ΔRAP/ΔPAWP was 0.6 mmHg/L/min. Conclusions Most patients with ATTR-CM have isolated post-capillary or combined pre- and post-capillary PH at rest, and almost all patients develop exercise-induced PH with a large post-capillary component. There was a pronounced, but balanced increase in atrial pressures on exercise.

• Solberg, Ole Geir; Aaberge, Lars; Bosse, Gerhard; Ueland, Thor; Gullestad, Lars & Aukrust, Pål [Vis alle 7 forfattere av denne artikkelen] (2023). Microvascular function and inflammatory activation in Takotsubo cardiomyopathy. ESC Heart Failure. 10(5), s. 3216–3222. doi: 10.1002/ehf2.14461. Fulltekst i vitenarkiv Vis sammendrag

  Aims - The aim of this study was to determine microvascular function in the acute phase of Takotsubo syndrome (TTS) and to identify inflammatory mediators that could reflect TTS-induced pathology.<p> <p>Methods and results - The study included 20 females [median age 65 years; interquarile range (IQR) = 58–70 years] with TTS according to the Mayo diagnostic criteria. During heart catheterization, we determined the index of microvascular resistance (IMR) and drew blood samples almost simultaneously from the aorta and coronary sinus. Cardiac magnetic resonance imaging (MRI) was done in the acute phase. We present descriptive coronary physiology and cardiac MRI data and compare inflammatory biomarkers between samples from the aorta, coronary sinus, and venous samples after 3 months using the Wilcoxon signed-rank test. For comparison, we also analysed the actual biomarkers in venous blood from 15 healthy female controls. A supplementary analysis explored Spearman's rank correlation between the inflammatory biomarkers, IMR, MRI data, and cardiac biomarkers. The median IMR was 16.5 mmHg·s (IQR = 10.5–28.2 mmHg·s), which was only slightly higher than that in the reference populations. Seven (35%) of the study subjects had IMR > 25 mmHg·s, suggesting a microvascular dysfunction. IMR was not affected by time from symptom onset. According to MRI, the apical region of the left ventricle was affected in 65% of the subjects. The median ejection fraction was 41% (IQR = 31–48%). Biomarker analyses revealed elevation of markers for extracellular matrix remodelling and fibrosis, inflammation, immune activation, and upstream inflammation as compared with healthy controls. Only the levels of interleukin (IL)-1 receptor antagonist and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) were higher in the coronary sinus than in the aorta. No variable was significantly correlated with IMR. The IL-6 level in the aorta was inversely correlated with the left ventricular ejection fraction. Growth differentiation factor-15, osteoprotegerin, and von Willebrand factor levels in both aorta and coronary sinus were positively correlated with N-terminal-pro-brain-natriuretic peptide, while the correlations of IL-6 and sTIM-3 with N-terminal-pro-brain-natriuretic peptide were restricted to the aorta and coronary sinus, respectively. While most of the markers were within normal limits after 3 months, matrix metalloproteinase-9 increased during follow-up to reach levels higher than those in the healthy controls.<p> <p>Conclusion - The median IMR was only slightly elevated in this study, but about one-third of the patients had values indicating microvascular dysfunction. The present study supports the involvement of several inflammatory pathways in TTS, including monocyte/macrophage activation, with sTIM-3 as a potential novel marker.

• Ofstad, Anne Pernille; Brunborg, Cathrine; Johansen, Odd Erik; Mørkedal, Bjørn; Fagerland, Morten & Laugsand, Lars Erik [Vis alle 8 forfattere av denne artikkelen] (2023). Development of a tool to predict the risk of incident heart failure in a general population: the HUNT for HF risk score. ESC Heart Failure. 10(5), s. 2807–2815. doi: 10.1002/ehf2.14390. Fulltekst i vitenarkiv Vis sammendrag

  Aims Currently, no incident heart failure (HF) risk score that is in regular use in a general population is available. We aimed to develop this and compare with existing HF risk scores. Methods and results Participants in the third wave (2006–08) of the population-based Trøndelag Health Study 3 (HUNT3) were included if they reported no previous HF. Any hospital diagnoses captured during follow-up (until the end of 2018) of HF, cardiomyopathy, or hypertensive heart disease were assessed by an experienced cardiologist. Valid HF events were defined as symptoms/signs of HF and objective evidence of structural/functional abnormality of the heart at rest. The model was compared with slightly modified HF risk scores (the Health Aging and Body Composition HF risk score, the Framingham HF risk score, the Pooled Cohort equations to Prevent HF risk score, and NORRISK 2). Among 36 511 participants (mean ± SD age of 57.9 ± 13.3 years, 55.4% female), with a mean follow-up of 10.2 ± 1.3 years, 1366 developed HF (incidence rate of 3.66 per 1000 participant years). Out of the 38 relevant clinical variables assessed, we identified 12 (atrial fibrillation being the strongest) that independently predicted an HF event. The final model demonstrated good discrimination (C statistics = 0.904) and calibration, was stable in internal validation, and performed well compared with existing risk scores. The model identified that, at enrolment, 31 391 (86%), 2386 (7%), 1246 (3%), and 1488 (4%) had low, low-intermediate, high-intermediate, and high 10-year HF risk, respectively. Conclusions Twelve clinical variables independently predicted 10-year HF risk. The model may serve well as the foundation of a practical, online risk score for HF in general practice.

• Prapiadou, Savvina; Živković, Luka; Thorand, Barbara; George, Marc J.; Laan, Sander W Van Der & Malik, Rainer [Vis alle 20 forfattere av denne artikkelen] (2023). Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis. Circulation. ISSN 0009-7322. 149(9), s. 669–683. doi: 10.1161/CIRCULATIONAHA.123.064974. Fulltekst i vitenarkiv Vis sammendrag

  Background: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. Methods: Leveraging data from 522 681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6R (IL-6 receptor) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization, we assessed its effects on 3281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3301). Using mediation Mendelian randomization, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. Results: We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 (C-X-C motif chemokine ligand 10) were associated with risk of coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease, with up to 67% of the effects of genetically downregulated IL-6 signaling on these end points mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. Conclusions: Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ–inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in 3 vascular compartments and, as such, could serve as a promising drug target for atheroprotection.

• Krämer, Bernhard K.; Hauske, Sibylle J.; Chilton, Robert; Mann, Johannes F.E.; Gullestad, Lars & Fitchett, David [Vis alle 9 forfattere av denne artikkelen] (2023). Changes in cardiac and vascular haemodynamics as potential mediators of improvements in cardiovascular and kidney outcomes with empagliflozin in type 2 diabetes. Journal of Diabetes and its Complications (JDC). ISSN 1056-8727. 37(9). doi: 10.1016/j.jdiacomp.2023.108588. Fulltekst i vitenarkiv Vis sammendrag

  Aims Evaluate changes in haemodynamic markers as mediators of cardiovascular (CV) and kidney benefits with empagliflozin. Methods Post-hoc analysis of EMPA-REG OUTCOME in patients with type 2 diabetes (T2D) and established CV disease receiving empagliflozin (10 and 25 mg) or placebo. Outcomes were CV death, hospitalisation for heart failure [HF], HF death, incident/worsening nephropathy, new onset macroalbuminuria, and the composite of sustained estimated glomerular filtration rate decline ≥40 % from baseline, renal replacement therapy or renal death. To be considered a mediator, changes in variable (pulse pressure, mean arterial pressure and cardiac workload) over time had to be (1) affected by active treatment, (2) associated with the outcome, and (3) adjustment for changes over time must reduce treatment effect versus an unadjusted analysis. Variables were evaluated in Cox regression analyses. Results Pulse pressure, mean arterial pressure and cardiac workload were significantly reduced by empagliflozin vs placebo. Using change from baseline to Week 12 or sensitivity analyses (time-dependent updated mean and current change from baseline) of these CV parameters, only small impacts on empagliflozin effect on CV and kidney outcomes were shown. Conclusions Improvements in haemodynamic parameters did not substantially mediate empagliflozin benefits on CV and kidney outcomes in patients with T2DM and established CV disease.

• Kristiansen, Stein; Nikolaidis, Konstantinos; Plagemann, Thomas Peter; Goebel, Vera Hermine; Traaen, Gunn Marit & Øverland, Britt [Vis alle 14 forfattere av denne artikkelen] (2023). A clinical evaluation of a low-cost strain gauge respiration belt and machine learning to detect sleep apnea. Smart Health. ISSN 2352-6483. 27. doi: 10.1016/j.smhl.2023.100373. Fulltekst i vitenarkiv Vis sammendrag

  Sleep apnea is a common and severe sleep-related respiratory disorder. Since the symptoms of sleep apnea are often ambiguous, it is difficult for a physician to decide whether to prescribe a clinical diagnosis, i.e., polysomnography (PSG), which results in a large percentage of undiagnosed and very late diagnosed cases. To reduce the time to diagnosis we investigate whether sleep monitoring data collected with a low-cost strain gauge respiration belt (called Flow) and a smartphone can be used to estimate with machine learning (ML) the severity of a patient’s sleep apnea. The Flow belt and the Type III sleep monitor Nox T3 were used together by 29 patients for unattended sleep monitoring at home, resulting each in 235 hours of sleep data. Through experimental analysis, we found that Convolutional Neural Networks are best suited to analyze the Flow data, because they are most robust against the frequently occurring baseline issues and exhibit the best performance with an accuracy of 0.7609, sensitivity of 0.7833, and specificity of 0.7217. These results can be achieved even if the classifier is trained only on high-quality data from the Nox T3. Thus, there are good chances that future ML experiments with data from other low-cost respiration belts can benefit from existing open PSG datasets without new extensive data collection. On a low-end smartphone, the classifier needs approximately one second to analyze the sleep data from one night. The results demonstrate the potential of low-cost strain gauge belts, smartphones, and ML to enable large parts of the population to perform sleep apnea pre-screening at home.

• Massey, Richard; Myrdal, Ole Henrik; Diep, Phoi Phoi; Dirdal, Marta Maria; Brinch, Lorentz & Gullestad, Lars [Vis alle 9 forfattere av denne artikkelen] (2022). Reduced exercise capacity is associated with left ventricular systolic dysfunction in long-term survivors of allogeneic hematopoietic stem-cell transplantation. Journal of Clinical Ultrasound. ISSN 0091-2751. 51(1), s. 5–15. doi: 10.1002/jcu.23264. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Exercise intolerance is a common complication in survivors of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The aim of this study was to determine if cardiac function measured with echocardiography is associated with exercise capacity measured with cardio-pulmonary exercise tests in long-term survivors treated in their youth with allo-HSCT. Methods The study included 96 patients, of which 54.2% were female, aged 34.9 ± 11.6 years and 17.7 ± 9.3 years after allo-HSCT. Reduced exercise capacity was defined as <85% of predicted-peak oxygen uptake (VO2peak). Linear regression was used in the prediction of VO2peak (ml/kg/min). Receiver operating characteristic evaluated the accuracy of predicting reduced exercise capacity. Results VO2peak was 36.2 ± 7.7 ml/kg/min and 43 (44.8%) had reduced exercise capacity. Left ventricular ejection fraction was 55.4 ± 5.9% and global longitudinal strain (GLS) was −17.6% ± 2.0%. Left and right ventricular functions were significantly lower in survivors with reduced exercise capacity. Increased body mass index, lower physical activity score, reduced pulmonary function (by forced expiratory volume in 1-s) and reduced left ventricular systolic function (by GLS) were significant independent predictors for reduced VO2peak. GLS was superior to other echocardiographical indices for identifying reduced exercise capacity (area under curve = 0.64, p = 0.014). Conclusions Left ventricular systolic dysfunction measured by GLS is associated with reduced exercise capacity in long-term allo-HSCT survivors.

• Hunt, Tove Elizabeth Frances; Traaen, Gunn Marit; Aakerøy, Lars; Bendz, Christina; Øverland, Britt & Akre, Harriet [Vis alle 15 forfattere av denne artikkelen] (2022). Effect of continuous positive airway pressure therapy on recurrence of atrial fibrillation after pulmonary vein isolation in patients with obstructive sleep apnea: A randomized controlled trial. Heart Rhythm. ISSN 1547-5271. 19(9), s. 1433–1441. doi: 10.1016/j.hrthm.2022.06.016. Fulltekst i vitenarkiv Vis sammendrag

  Background Obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Whether treatment with continuous positive airway pressure (CPAP) reduces AF recurrence after catheter ablation with pulmonary vein isolation (PVI) is unknown. Objective The purpose of this study was to assess the effect of CPAP treatment on the recurrence and burden of AF after PVI in patients with OSA. Methods We randomized patients with paroxysmal AF and an apnea-hypopnea index (AHI) ≥15 events/hour to treatment with CPAP or standard care. Heart rhythm was monitored by an implantable loop recorder. AF recurrence after PVI was defined as any episode of AF lasting >2 minutes after a 3-month blanking period. Results PVI was performed in 83 patients. Thirty-seven patients were randomized to CPAP treatment and 46 patients to standard care. The AHI was reduced from 26.7 ± 14 events/hour to 1.7 ± 1.3 events/hour at follow-up in the CPAP group (P = .001). A total of 57% of patients in both the CPAP group and the standard care group had at least 1 episode of AF 3–12 months after PVI (P for difference = 1). AF burden after ablation was reduced in both groups, with no between-group difference (P = .69). Conclusion In patients with paroxysmal AF and OSA, treatment with CPAP did not further reduce the risk of AF recurrence after ablation. PVI considerably reduced the burden of AF in OSA patients, without any difference between groups.

• Nygaard, Sissel; Christensen, Anders Haugom; Sletner, Line; Rolid, Katrine; Nytrøen, Kari & Gullestad, Lars [Vis alle 11 forfattere av denne artikkelen] (2022). Predictors of Hypertension Development 1 Year after Heart Transplantation. Transplantation. ISSN 0041-1337. 106(8), s. 1656–1665. doi: 10.1097/TP.0000000000004068. Fulltekst i vitenarkiv
• Fontaine, Margaux A. C.; Jin, Han; Gagliardi, Mick; Rousch, Mat; Wijnands, Erwin & Stoll, Monika [Vis alle 23 forfattere av denne artikkelen] (2022). Blood Milieu in Acute Myocardial Infarction Reprograms Human Macrophages for Trauma Repair. Advanced Science. s. 1–14. doi: 10.1002/advs.202203053. Fulltekst i vitenarkiv Vis sammendrag

  Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts the whole body, including blood. This study addresses whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages are exposed to 20% human AMI (n = 50) or control (n = 20) serum and analyzed by transcriptional and multiparameter functional screening followed by network-guided data interpretation and drug repurposing. Results are validated in an independent cohort at functional level (n = 47 AMI, n = 25 control) and in a public dataset. AMI serum exposure results in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, gene networks associated with AMI and with poor clinical prognosis in AMI are identified. Network-guided drug screening on the latter unveils prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. The results demonstrate pronounced context-induced macrophage reprogramming by the AMI systemic environment, to a degree decisive for patient prognosis. This offers new opportunities for targeted intervention and optimized cardiovascular disease risk management.

• Vergaro, Giuseppe; Gentile, Francesco; Aimo, Alberto; Januzzi, James L.; Richards, A. Mark & Lam, Carolyn S.P. [Vis alle 39 forfattere av denne artikkelen] (2022). Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure. ESC Heart Failure. 9(4), s. 2084–2095. doi: 10.1002/ehf2.13883. Fulltekst i vitenarkiv Vis sammendrag

  Aims To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NTproBNP) in women and men with chronic heart failure (HF).<p> <p>Methods and results Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. <p>Conclusions In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

• Englund, Kristine Victoria Brautaset; Østby, Carol Margaret; Broch, Kaspar; Ueland, Thor; Aukrust, Pål & Gude, Einar [Vis alle 8 forfattere av denne artikkelen] (2022). Iron homeostasis in heart transplant recipients randomized to ferric derisomaltose or placebo. Clinical Transplantation. ISSN 0902-0063. 36(7). doi: 10.1111/ctr.14695. Fulltekst i vitenarkiv Vis sammendrag

  Introduction The randomized IronIC trial evaluated the effect of intravenous ferric derisomaltose on physical capacity in iron-deficient, maintenance heart transplant (HTx) recipients. Iron deficiency was defined as in heart failure with high cut-points for ferritin to compensate for inflammation. However, intravenous iron did not improve physical capacity except in patients with ferritin <30 μg/L. We aimed to explore determinants of iron status in the 102 IronIC participants to better define iron deficiency in the HTx population. Methods We assessed key governors of iron homeostasis, such as hepcidin, soluble transferrin receptor (sTfR), and interleukin-6 (IL-6). We also measured growth factors and inflammatory markers with relevance for iron metabolism. The results were compared to those of 21 healthy controls. Results Hepcidin did not differ between HTx recipients and controls, even though markers of inflammation were modestly elevated. However, HTx recipients with ferritin <30 μg/L or sTfR above the reference range had significantly reduced hepcidin levels suggestive of true iron deficiency. In these patients, intravenous iron improved peak oxygen uptake. Hepcidin correlated positively with ferritin and negatively with sTfR. Conclusion HTx recipients with iron deficiency as defined in heart failure do not have elevated hepcidin levels, although inflammatory markers are modestly increased. The high ferritin cut-offs used in heart failure may not be suitable to define iron deficiency in the HTx population. We suggest that hepcidin and sTfR should be measured to identify patients with true iron deficiency, who might benefit from treatment with intravenous iron.

• Huse, Camilla; Anstensrud, Anne Kristine; Michelsen, Annika Elisabet; Ueland, Thor; Broch, Kaspar & Woxholt, Sindre [Vis alle 29 forfattere av denne artikkelen] (2022). Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial. EBioMedicine. 80(104013). doi: 10.1016/j.ebiom.2022.104013. Fulltekst i vitenarkiv Vis sammendrag

  We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. Methods In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). Findings (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. Interpretation Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage.

• Kvaslerud, Anette Borger; Gude, Einar; Erikssen, Gunnar; Andreassen, Arne K.; Gullestad, Lars & Broch, Kaspar (2022). Diastolic Dysfunction Is Unmasked on Exercise in Patients with Asymptomatic, Severe Aortic Stenosis: An Invasive Hemodynamic Study. Circulation: Heart Failure. ISSN 1941-3289. 15(2), s. E009253–E009253. doi: 10.1161/CIRCHEARTFAILURE.121.009253. Fulltekst i vitenarkiv Vis sammendrag

  Background: Optimal timing of aortic valve replacement remains difficult in patients with asymptomatic, severe aortic stenosis (AS). More accurate diagnostic methods are warranted for the detection of subtle ventricular impairment. We aimed to evaluate diastolic function in asymptomatic patients with severe AS. Methods: In this cross-sectional study, patients with asymptomatic, severe AS were evaluated with right heart catheterization at rest and during moderate exercise. The patients also underwent cardiopulmonary exercise testing to objectify functional capacity and confirm the absence of symptoms. Results: Between February 2019 and May 2021, we included 50 patients aged 70±12 years. The patients had severe AS with peak velocity 4.4±0.4 m/s, mean gradient 46±9 mm Hg, and an indexed valve area of 0.47±0.08 cm2 at rest. All patients were asymptomatic and had normal left ventricular ejection fraction. Five patients had postcapillary pulmonary hypertension at rest. During exercise, 44 patients (88%) had an increase in the mean pulmonary artery pressure per increase in cardiac output of >3 mm Hg/L per minute, of whom 93% had a concomitant increase in the pulmonary artery wedge pressure per increase in cardiac output >2 mm Hg/L per minute, suggesting exercise-induced pulmonary hypertension due to left heart disease. Female gender and increasing age were associated with a higher increase in the pulmonary artery wedge pressure per increase in cardiac output ratio. The catheterization was well tolerated, and there were no adverse events. Conclusions: A large proportion of asymptomatic patients with severe, degenerative AS have exercise-induced postcapillary pulmonary hypertension.

• Kvaslerud, Anette Borger; Bardan, Sara; Andresen, Kristoffer; Kløve, Sophie Foss; Fagerland, Morten & Edvardsen, Thor [Vis alle 8 forfattere av denne artikkelen] (2022). Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for transcatheter aortic valve implantation: results of the IIISAS randomised trial. European Journal of Heart Failure. ISSN 1388-9842. 24(7), s. 1269–1279. doi: 10.1002/ejhf.2557. Fulltekst i vitenarkiv Vis sammendrag

  Aims The aim of this trial was to evaluate whether intravenous iron could provide benefit beyond transcatheter aortic valve implantation (TAVI) in iron-deficient patients with severe aortic stenosis. Methods and results In this randomised, placebo-controlled, double-blind, single-centre trial, we enrolled patients with severe aortic stenosis and iron deficiency (defined as ferritin <100 µg/L, or 100–299 µg/L with a transferrin saturation <20%) who were evaluated for TAVI. Patients were randomly assigned (1:1) to receive intravenous ferric derisomaltose or placebo ∼3 months before TAVI. The primary endpoint was the between-group, baseline-adjusted 6-min walk distance measured 3 months after TAVI. Secondary outcomes included quality of life, iron stores, hand grip strength, New York Heart Association (NYHA) class, and safety. Between January 2020 and September 2021, we randomised 74 patients to ferric derisomaltose and 75 patients to placebo. The modified intention-to-treat population comprised the 104 patients who completed the 6-min walk test at baseline and 3 months after successful TAVI. Iron stores were restored in 76% of the patients allocated to iron and 13% of the patients allocated to placebo (p < 0.001). There was no difference in the baseline-adjusted 6-min walk distance between the two treatment arms (p = 0.82). The number of serious adverse events, quality of life, hand grip strength, and NYHA class did not differ between the treatment arms. Conclusion Treatment with intravenous iron did not provide clinical benefit beyond TAVI in iron-deficient patients with severe aortic stenosis. Clinical Trial Registration: ClinicalTrials.gov NCT04206228.

• Baysa, Anton; Maghazachi, Azzam; Sand, Kristin Larsen; Campesan, Marika; Zaglia, Tania & Mongillo, Marco [Vis alle 13 forfattere av denne artikkelen] (2022). Toll-like receptor 9 signaling after myocardial infarction: Role of p66ShcA adaptor protein. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 644, s. 70–78. doi: 10.1016/j.bbrc.2022.12.085. Fulltekst i vitenarkiv Vis sammendrag

  During myocardial infarction, cellular debris is released, causing a sterile inflammation via pattern recognition receptors. These reactions amplify damage and promotes secondary heart failure. The pattern recognition receptor, Toll-like receptor 9 (TLR9) detects immunogenic fragments of endogenous DNA, inducing inflammation by NFκB. The p66ShcA adaptor protein plays an important role in both ischemic myocardial damage and immune responses. We hypothesized that p66ShcA adaptor protein promotes DNA-sensing signaling via the TLR9 pathway after myocardial infarction. TLR9 protein expression increased in cardiac tissue from patients with end-stage heart failure due to ischemic heart disease. Myocardial ischemia in mice in vivo induced gene expression of key TLR9 pathway proteins (MyD88 and Unc93b1). In this model, a functional link between TLR9 and p66ShcA was revealed as; (i) ischemia-induced upregulation of TLR9 protein was abrogated in myocardium of p66ShcA knockout mice; (ii) when p66ShcA was overexpressed in NFkB reporter cells stably expressing TLR9, NFkB-activation increased during stimulation with the TLR9 agonist CpG B; (iii) in cardiac fibroblasts, p66ShcA overexpression caused TLR9 upregulation. Co-immunoprecipitation showed that ShcA proteins and TLR9 may be found in the same protein complex, which was dissipated upon TLR9 stimulation in vivo. A proximity assay confirmed the co-localization of TLR9 and ShcA proteins. The systemic immune response after myocardial ischemia was dampened in p66ShcA knockout mice as interleukin-4, -17 and −22 expression in mononuclear cells isolated from spleens was reduced. In conclusion, p66ShcA adaptor may be an interaction partner and a regulator of the TLR9 pathway post-infarction.

• Vergaro, Giuseppe; Gentile, Francesco; Meems, Laura M.G.; Aimo, Alberto; Januzzi, James L. & Richards, A. Mark [Vis alle 39 forfattere av denne artikkelen] (2021). NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories. JACC. Heart failure. ISSN 2213-1779. 9(9), s. 653–663. doi: 10.1016/j.jchf.2021.05.014. Fulltekst i vitenarkiv
• Ahn, Jung-Min; Zimmermann, Frederik M.; Gullestad, Lars; Angerås, Oskar; Karason, Kristjan & Russell, Kristoffer [Vis alle 17 forfattere av denne artikkelen] (2021). Microcirculatory Resistance Predicts Allograft Rejection and Cardiac Events After Heart Transplantation. Journal of the American College of Cardiology. ISSN 0735-1097. 78(24), s. 2425–2435. doi: 10.1016/j.jacc.2021.10.009. Fulltekst i vitenarkiv
• Christensen, Anders Haugom; Nygaard, Sissel; Rolid, Katrine; Nytrøen, Kari; Gullestad, Lars & Fiane, Arnt Eltvedt [Vis alle 10 forfattere av denne artikkelen] (2021). Strong evidence for parasympathetic sinoatrial reinnervation after heart transplantation. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. s. 1–12. doi: 10.1016/j.healun.2021.11.005. Fulltekst i vitenarkiv Vis sammendrag

  Background Heart transplantation (HTx) surgically denervates the heart. We examined indices of sinoatrial reinnervation, with emphasis on (1) the occurrence and timing of parasympathetic reinnervation, and (2) the consequences of reinnervation for heart rate (HR) responsiveness and arterial baroreceptor sensitivity. Methods Fifty HTx recipients were prospectively followed for 36 months after surgery. Hemodynamic variables and heart rate variability were continuously recorded at supine rest, 60 degrees head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. Results Suggesting parasympathetic reinnervation: at baseline rest, root of the mean squared differences of successive RR intervals increased from median 3.9(5.9) to 7.1(5.1) ms (p < 0.001); high-frequency power increased from 4.0(12) to 5.7(18.9) ms2 (p = 0.018); and baroreceptor sensitivity increased from 0.04(0.36) to 1.3(2.4) ms/mmHg (p < 0.001). Suggesting sympathetic reinnervation: at baseline rest low-frequency power increased from 0.49(2.5) to 7.5(18.1) ms2 (p < 0.001); and HR responses to sympathetic stimulation during (1) head-up tilt increased from 1.9(4.2) to 9.1(8.2) bpm (p < 0.001), (2) Valsalva increased from 1.6(1.4) to 8.3(10.8) bpm (p < 0.001) and (3) handgrip increased from 0.3(0.6) to 1.9(5.1) bpm (p < 0.001). Signs of sympathetic reinnervation emerged within 6 months, while signs of parasympathetic reinnervation emerged by 24 months. Conclusions Root of the mean squared differences of successive RR intervals, high-frequency and low-frequency variability, HR responsiveness and arterial baroreflex sensitivity all increased after HTx, suggesting functional parasympathetic and sympathetic sinoatrial reinnervation. Accordingly, the pathological regulatory state present in heart transplant recipients, which is responsible for a host of functional and clinical abnormalities, is being partially offset over time by restored autonomic control of the heart in many heart transplant recipients.

• Ueland, Thor; Gullestad, Lars; Kou, Lei; Young, James B.; Pfeffer, Marc A. & Veldhuisen, Dirk J. van [Vis alle 11 forfattere av denne artikkelen] (2021). Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF. Clinical Research in Cardiology. ISSN 1861-0684. s. 1–11. doi: 10.1007/s00392-021-01944-6. Fulltekst i vitenarkiv Vis sammendrag

  Aims - We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia<p> <p>Methods and results - Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23–1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38–2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin.<p> <p>Conclusions - In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.

• Kristiansen, Stein; Nikolaidis, Konstantinos; Plagemann, Thomas Peter; Goebel, Vera Hermine; Traaen, Gunn Marit & Øverland, Britt [Vis alle 14 forfattere av denne artikkelen] (2021). Machine learning for sleep apnea detection with unattended sleep monitoring at home. ACM Transactions on Computing for Healthcare (HEALTH). ISSN 2691-1957. 2(2). doi: 10.1145/3433987. Fulltekst i vitenarkiv Vis sammendrag

  Sleep apnea is a common and strongly under-diagnosed severe sleep-related respiratory disorder with periods of disrupted or reduced breathing during sleep. To diagnose sleep apnea, sleep data are collected with either polysomnography or polygraphy and scored by a sleep expert. We investigate in this work the use of supervised machine learning to automate the analysis of polygraphy data from the A3 study containing more than 7,400 hours of sleep monitoring data from 579 patients. We conduct a systematic comparative study of classification performance and resource use with different combinations of 27 classifiers and four sleep signals. The classifiers achieve up to 0.8941 accuracy (kappa: 0.7877) when using all four signal types simultaneously and up to 0.8543 accuracy (kappa: 0.7080) with only one signal, i.e., oxygen saturation. Methods based on deep learning outperform other methods by a large margin. All deep learning methods achieve nearly the same maximum classification performance even when they have very different architectures and sizes. When jointly accounting for classification performance, resource consumption and the ability to achieve with less training data high classification performance, we find that convolutional neural networks substantially outperform the other classifiers.

• Kristiansen, Stein; Goebel, Vera Hermine; Andersen, Morten Hamborg; Plagemann, Thomas Peter; Traaen, Gunn Marit & Øverland, Britt [Vis alle 8 forfattere av denne artikkelen] (2021). Evaluating a Low-Cost Strain Gauge Breathing Sensor for Sleep Apnea Detection at Home. I Gedeon, Ibrahim (Red.), 2021 IEEE International Conference on Communications Workshops (ICC Workshops). IEEE (Institute of Electrical and Electronics Engineers). ISSN 9781728194417. doi: 10.1109/ICCWorkshops50388.2021.9473597. Fulltekst i vitenarkiv Vis sammendrag

  We report results and experience from a clinical evaluation of a low-cost strain gauge breathing sensor for sleep apnea detection. We collected from 34 individuals 57 nights of unattended sleep monitoring data at home with the certified Type 3 monitor Nox-T3 and the Flow strain gauge sensor from SweetZpot. The quality of the Flow data does not match the quality of the Nox-T3 data due to the much simpler build of the Flow sensor and issues during data acquisition. The Flow data can still be used to accurately discriminate between normal and disrupted breathing. With appropriate data pre-processing, we achieve a mean breath detection sensitivity of 97.2% and positive prediction value of 94.2%.

• Christensen, Anders Haugom; Nygaard, Sissel Irene; Rolid, Katrine; Nytrøen, Kari; Gullestad, Lars & Fiane, Arnt [Vis alle 10 forfattere av denne artikkelen] (2021). Early Signs of Sinoatrial Reinnervation in the Transplanted Heart. Transplantation. ISSN 0041-1337. 105(9), s. 2086–2096. doi: 10.1097/TP.0000000000003580. Fulltekst i vitenarkiv
• Olsen, Maria Belland; Gregersen, Ida; Sandanger, Øystein; Yang, Kuan; Sokolova, Marina & Halvorsen, Bente E. [Vis alle 10 forfattere av denne artikkelen] (2021). Targeting the Inflammasome in Cardiovascular Disease. JACC: Basic to Translational Science. ISSN 2452-302X. 7(1), s. 84–98. doi: 10.1016/j.jacbts.2021.08.006. Fulltekst i vitenarkiv Vis sammendrag

  The pathogenesis of cardiovascular disease (CVD) is complex and multifactorial, and inflammation plays a central role. Inflammasomes are multimeric protein complexes that are activated in a 2-step manner in response to infection or tissue damage. Upon activation the proinflammatory cytokines, interleukins-1β and -18 are released. In the last decade, the evidence that inflammasome activation plays an important role in CVD development became stronger. We discuss the role of different inflammasomes in the pathogenesis of CVD, focusing on atherosclerosis and heart failure. This review also provides an overview of existing experimental studies and clinical trials on inflammasome inhibition as a therapeutic target in these disorders.

• Frisk, Michael; Le, Christopher; Shen, Xin; Røe, Åsmund Treu; Hou, Yufeng & Manfra, Ornella [Vis alle 24 forfattere av denne artikkelen] (2021). Etiology-dependent impairment of diastolic cardiomyocyte calcium homeostasis in heart failure with preserved ejection fraction. Journal of the American College of Cardiology. ISSN 0735-1097. 77(4), s. 405–419. doi: 10.1016/j.jacc.2020.11.044. Fulltekst i vitenarkiv Vis sammendrag

  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 Ca2+ 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 Ca2+ 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 Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. Conclusions Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

• Massey, Richard; Diep, Phoi Phoi; Dirdal, Marta Maria; Kvaslerud, Anette Borger; Brinch, Lorentz & Aakhus, Svend [Vis alle 9 forfattere av denne artikkelen] (2021). Impaired right ventricular function in long-term survivors of allogeneic haematopoietic stem-cell transplantation. Open heart. 8(2), s. 1–11. doi: 10.1136/openhrt-2021-001768. Fulltekst i vitenarkiv Vis sammendrag

  Aims Survivors of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) are at higher risk of cardiovascular disease. We aimed to describe right ventricular (RV) systolic function and risk factors for RV dysfunction in long-term survivors of allo-HSCT performed in their youth. Methods and results This cohort included 103 survivors (53% female), aged (mean±SD) 17.6±9.5 years at allo-HSCT, with a follow-up time of 17.2±5.5 years. Anthracyclines were used as first-line therapy for 44.7% of the survivors. The RV was evaluated with echocardiography, and found survivors to have reduced RV function in comparison to a group of healthy control subjects: Tricuspid annular plane systolic excursion, (TAPSE, 20.8±3.7 mm vs 24.6±3.8 mm, p<0.001), RV peak systolic velocity (RV-s’, 11.2±2.3 cm/s vs 12.3±2.3 cm/s, p=0.001), fractional area change (FAC, 41.0±5.2% vs 42.2±5.1%, p=0.047) and RV free-wall strain (RVFWS, −27.1±4.2% vs −28.5±3.3%, p=0.043). RV systolic dysfunction (RVSD) was diagnosed in 14 (13.6%), and was strongly associated with progressive left ventricular systolic dysfunction (LVSD). High dosages of anthracyclines were associated with greater reductions in RV and LV function. Multivariable linear regressions confirmed global longitudinal strain to be a significant independent predictor for reduced RV function. Conclusion Impaired RV function was found in long-term survivors of allo-HSCT who were treated in their youth. This was associated with progressive left ventricle dysfunction, and pretransplant therapies with anthracyclines. The occurrence of RVSD was less frequent and was milder than coexisting LVSD in this cohort.

• Ahn, Jung-Min; Zimmermann, Frederik M.; Arora, Satish; Solberg, Ole Geir; Angerås, Oskar & Rolid, Katrine [Vis alle 19 forfattere av denne artikkelen] (2021). Prognostic value of comprehensive intracoronary physiology assessment early after heart transplantation. European Heart Journal. ISSN 0195-668X. 42(48), s. 4918–4929. doi: 10.1093/eurheartj/ehab568. Fulltekst i vitenarkiv
• Englund, Kristine Victoria Brautaset; Østby, Charlotte M.; Rolid, Katrine; Gude, Einar; Andreassen, Arne K. & Gullestad, Lars [Vis alle 7 forfattere av denne artikkelen] (2021). Intravenous iron supplement for iron deficiency in cardiac transplant recipients (IronIC): A randomized clinical trial. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. 40(5), s. 1–9. doi: 10.1016/j.healun.2021.01.1390. Fulltekst i vitenarkiv Vis sammendrag

  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%.

• Holt, Margrethe Flesvig; Michelsen, Annika Elisabet; Shahini, Negar; Bjørkelund, Elisabeth; Bendz, Christina & Massey, Richard J [Vis alle 15 forfattere av denne artikkelen] (2021). The Alternative Complement Pathway Is Activated Without a Corresponding Terminal Pathway Activation in Patients With Heart Failure. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.800978. Fulltekst i vitenarkiv Vis sammendrag

  Objective Dysregulation of the complement system has been described in patients with heart failure (HF). However, data on the alternative pathway are scarce and it is unknown if levels of factor B (FB) and the C3 convertase C3bBbP are elevated in these patients. We hypothesized that plasma levels of FB and C3bBbP would be associated with disease severity and survival in patients with HF. Methods We analyzed plasma levels of FB, C3bBbP, and terminal C5b-9 complement complex (TCC) in 343 HF patients and 27 healthy controls. Results Compared with controls, patients with HF had elevated levels of circulating FB (1.6-fold, p &lt; 0.001) and C3bBbP (1.3-fold, p &lt; 0.001). In contrast, TCC, reflecting the terminal pathway, was not significantly increased (p = 0.15 vs controls). FB was associated with NT-proBNP, troponin, eGFR, and i.e., C-reactive protein. FB, C3bBbP and TCC were not associated with mortality in HF during a mean follow up of 4.3 years. Conclusion Our findings suggest that in patients with HF, the alternative pathway is activated. However, this is not accompanied by activation of the terminal pathway.

• Ueland, Thor; Abraityte, Judita Aurelija; Norum, Hilde Margrethe; Sharanga, Varathalingam; Gullestad, Lars & Aukrust, Pål [Vis alle 7 forfattere av denne artikkelen] (2021). Circulating regulators of the wingless pathway in precapillary pulmonary hypertension. Respirology (Carlton South. Print). ISSN 1323-7799. 26(6), s. 574–581. doi: 10.1111/resp.14048. Fulltekst i vitenarkiv Vis sammendrag

  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.<p> <p>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.<p> <p>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 (VO2). Finally, an elevation of Wnt5a and DKK3 during follow-up was independently associated with poor prognosis.<p> <p>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.

• Awoyemi, Ayodeji Olawale; Mayerhofer, Christiane Caroline; Felix, Alex S.; Hov, Johannes Espolin Roksund; Moscavitch, Samuel D. & Lappegård, Knut Tore [Vis alle 23 forfattere av denne artikkelen] (2021). Rifaximin or Saccharomyces boulardii in heart failure with reduced ejection fraction: Results from the randomized GutHeart trial. EBioMedicine. 70. doi: 10.1016/j.ebiom.2021.103511. Fulltekst i vitenarkiv Vis sammendrag

  Background The gut microbiota represents a potential treatment target in heart failure (HF) through microbial metabolites such as trimethylamine N-oxide (TMAO) and systemic inflammation. Treatment with the probiotic yeast Saccharomyces boulardii have been suggested to improve left ventricular ejection fraction (LVEF). Methods In a multicentre, prospective randomized open label, blinded end-point trial, we randomized patients with LVEF <40% and New York Heart Association functional class II or III, despite optimal medical therapy, to treatment (1:1:1) with the probiotic yeast Saccharomyces boulardii, the antibiotic rifaximin, or standard of care (SoC) only. The primary endpoint, the baseline-adjusted LVEF at three months, was assessed in an intention-to-treat analysis. Findings We enrolled a total of 151 patients. After three months’ treatment, the LVEF did not differ significantly between the SoC arm and the rifaximin arm (mean difference was -1•2 percentage points; 95% CI -3•2 - 0•7; p=0•22) or between the SoC arm and the Saccharomyces boulardii arm (mean difference -0•2 percentage points; 95% CI -2•2 - 1•9; p=0•87). We observed no significant between-group differences in changes in microbiota diversity, TMAO, or C-reactive protein. Interpretation Three months’ treatment with Saccharomyces boulardii or rifaximin on top of SoC had no significant effect on LVEF, microbiota diversity, or the measured biomarkers in our population with HF.

• Wyller, Vegard Bruun Bratholm; Nygaard, Sissel; Christensen, Anders Haugom; Rolid, Katrine; Nytrøen, Kari & Gullestad, Lars [Vis alle 10 forfattere av denne artikkelen] (2021). Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation. European Journal of Applied Physiology. ISSN 1439-6319. 121(3), s. 915–927. doi: 10.1007/s00421-020-04586-0. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Traaen, Gunn Marit; Aakerøy, Lars; Hunt, Tove Elizabeth Frances; Øverland, Britt; Bendz, Christina & Sande, Lars Øivind [Vis alle 16 forfattere av denne artikkelen] (2021). Effect of continuous positive airway pressure on arrhythmia in atrial fibrillation and sleep apnea a randomized controlled trial. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X. 204(5), s. 573–582. doi: 10.1164/rccm.202011-4133OC. Fulltekst i vitenarkiv Vis sammendrag

  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). A computerized system randomized eligible patients (1:1) to 5 months’ treatment with CPAP plus usual care (CPAP, n = 55) or usual care alone (control, n = 54). The outcome assessment was blinded. The planned primary outcome was the difference between CPAP treatment and control groups in change of AF burden (percentage 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%) had moderate to severe SA. Of these, 158 (65%) participated in the CPAP run-in period, of whom 39 (25%) patients did not tolerate the treatment. A total of 108 patients were available for the primary analysis. The mean time in AF decreased from 5.6% at baseline to 4.1% during the last 3 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 registered with www.clinicaltrials.gov (NCT02727192).

• Broch, Kaspar; Anstensrud, Anne Kristine; Woxholt, Sindre; Sharma, Kapil Kishore; Tøllefsen, Ingvild Maria & Bendz, Bjørn [Vis alle 23 forfattere av denne artikkelen] (2021). Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology. ISSN 0735-1097. 77(15), s. 1845–1855. doi: 10.1016/j.jacc.2021.02.049. Fulltekst i vitenarkiv Vis sammendrag

  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)

• Rafique, Muzammil; Solberg, Ole Geir; Gullestad, Lars; Bendz, Bjørn; Holm, Niels Ramsing & Neghabat, Omeed [Vis alle 10 forfattere av denne artikkelen] (2021). A randomized clinical study using optical coherence tomography to evaluate the short-term effects of high-intensity interval training on cardiac allograft vasculopathy: a HITTS substudy. Clinical Transplantation. ISSN 0902-0063. 36:e14488, s. 1–10. doi: 10.1111/ctr.14488. Fulltekst i vitenarkiv Vis sammendrag

  Cardiac allograft vasculopathy (CAV) remains a leading cause of long-term mortality after heart transplantation. Both preventive measures and treatment options are limited. This study aimed to evaluate the short-term effects of high-intensity interval training (HIT) on CAV in de novo heart transplant (HTx) recipients as assessed by optical coherence tomography (OCT). The study population was a subgroup of the 81-patient HITTS study in which HTx recipients were randomized to HIT or moderate intensity continuous training (MICT) for nine consecutive months. OCT images from baseline and 12 months were compared to assess CAV progression. The primary endpoint was defined as the change in the mean intima area. Paired OCT data were available for 56 patients (n = 23 in the HIT group and n = 33 in the MICT group). The intima area in the entire study population increased by 25% [from 1.8±1.4 mm2 to 2.3±2.0 mm2, P < .05]. The change was twofold higher in the MICT group (.6±1.2 mm2) than in the HIT group (.3±.6 mm2). However, the treatment effect of HIT was not significant (treatment effect = –.3 mm2, 95% CI [–.825 to .2 mm2] P = .29). These results suggest that early initiation of HIT compared with MICT does not attenuate CAV progression in de novo HTx recipients.

• Kristiansen, Oskar; Sverre, Elise Christine Bjørkholen; Peersen, Kari; Fagerland, Morten; Gjertsen, Erik & Gullestad, Lars [Vis alle 11 forfattere av denne artikkelen] (2021). The relationship between directly measured statin adherence, self-reported adherence measures and cholesterol levels in patients with coronary heart disease. Atherosclerosis. ISSN 0021-9150. 336, s. 23–29. doi: 10.1016/j.atherosclerosis.2021.09.020. Fulltekst i vitenarkiv Vis sammendrag

  Background and aims: We aimed to determine the relationship between statin adherence measured directly, and by self-report measures and serum cholesterol levels. Methods: Patients prescribed atorvastatin (N = 373) participated in a cross-sectional study 2–36 months after a coronary event. Self-reported adherence included statin adherence the past week, the 8-item Morisky medication adherence scale (MMAS-8), and the Gehi et al. adherence question. Atorvastatin was measured directly in spot blood plasma by a novel liquid chromatography tandem mass-spectrometry method discriminating adherence (0–1 doses omitted) and reduced adherence (≥2 doses omitted). Participants were unaware of the atorvastatin analyses at study participation. Results: Mean age was 63 (SD 9) years and 8% had reduced atorvastatin adherence according to the direct method. In patients classified with reduced adherence by the direct method, 40% reported reduced statin adherence, 32% reported reduced adherence with the MMAS-8 and 22% with the Gehi question. In those adherent by the direct method, 96% also reported high statin adherence, 95% reported high adherence on the MMAS-8 whereas 94% reported high adherence on the Gehi question. Cohen’s kappa agreement score with the direct method was 0.4 for self-reported statin adherence, 0.3 for the Gehi question and 0.2 for the MMAS-8. Adherence determined by the direct method, self-reported statin adherence last week, and the Gehi question was inversely related to LDL-cholesterol levels with a p-value of <0.001, 0.001 and 0.004, respectively. Conclusions: Plasma-statin measurements reveal reduced adherence with higher sensitivity than self-report measures, relate to cholesterol levels, and may prove to be a useful tool to improve lipid management.

• Abraham, William T.; Lindenfeld, JoAnn; Ponikowski, Piotr; Agostoni, Piergiuseppe; Butler, Javed & Desai, Akshay S. [Vis alle 27 forfattere av denne artikkelen] (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. European Heart Journal. ISSN 0195-668X. 42(6), s. 700–710. doi: 10.1093/eurheartj/ehaa943. Fulltekst i vitenarkiv
• Helseth, Ragnhild; Kleveland, Ola; Ueland, Thor; Wiseth, Rune; Damås, Jan Kristian & Broch, Kaspar [Vis alle 11 forfattere av denne artikkelen] (2021). Tocilizumab increases citrullinated histone 3 in non-ST segment elevation myocardial infarction. Open heart. 8(1). doi: 10.1136/openhrt-2020-001492. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Englund, Kristine Victoria Brautaset; Østby, Charlotte M.; Tjønnås, Gry; Gude, Einar; Andreassen, Arne K & Gullestad, Lars [Vis alle 7 forfattere av denne artikkelen] (2021). Prevalence of iron deficiency in heart transplant recipients. Clinical Transplantation. ISSN 0902-0063. s. 1–9. doi: 10.1111/ctr.14346. Fulltekst i vitenarkiv
• Kvaslerud, Anette Borger; Hussain, Amjad Iqbal; Auensen, Andreas; Fiane, Arnt E; Skulstad, Helge & Aaberge, Lars [Vis alle 8 forfattere av denne artikkelen] (2021). Outcomes in asymptomatic, severe aortic stenosis. PLOS ONE. doi: 10.1371/journal.pone.0249610. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Bürker, Britta Susanne; Malt, Ulrik Fredrik; Gude, Einar; Grov, Ingelin; Relbo, Anne & Dew, Mary Amanda [Vis alle 7 forfattere av denne artikkelen] (2021). Symptoms of anxiety after heart transplantation and their association with mortality: A secondary analysis. Clinical Transplantation. ISSN 0902-0063. 35(7), s. 1–7. doi: 10.1111/ctr.14323. Fulltekst i vitenarkiv
• Englund, Kristine Victoria Brautaset; Østby, Carol Margaret; Vartdal, Trond; Rolid, Katrine; Gude, Einar & Andreassen, Arne K. [Vis alle 8 forfattere av denne artikkelen] (2020). Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients (IronIC) - A Randomized, Double Blind, Controlled Trial. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. 39(4), s. S144–S144. doi: 10.1016/j.healun.2020.01.1067. Fulltekst i vitenarkiv
• Kristiansen, Stein; Traaen, Gunn Marit; Øverland, Britt; Plagemann, Thomas Peter; Gullestad, Lars & Akre, Harriet [Vis alle 14 forfattere av denne artikkelen] (2020). Comparing manual and automatic scoring of sleep monitoring data from portable polygraphy. Journal of Sleep Research. ISSN 0962-1105. doi: 10.1111/jsr.13036. Fulltekst i vitenarkiv Vis sammendrag

  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).

• Munkhaugen, John; Sverre, Elise Christine Bjørkholen; Peersen, Kari; Kristiansen, Oscar; Gjertsen, Erik & Gullestad, Lars [Vis alle 7 forfattere av denne artikkelen] (2020). Is the novel LDL-cholesterol goal <1.4 mmol/L achievable without a PCSK9 inhibitor in a chronic coronary population from clinical practice?. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 28(8), s. E10–E11. doi: 10.1177/2047487320923187. Fulltekst i vitenarkiv
• Rolid, Katrine; Andreassen, Arne K.; Yardley, Marianne; Bjørkelund, Elisabeth; Relbo, Anne & Grov, Ingelin [Vis alle 10 forfattere av denne artikkelen] (2020). Effect of High-Intensity Interval Training in De Novo Heart Transplant Recipients - 3-year Results from the HITTS Randomized Controlled Trial. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. 39(4), s. S224–S225. doi: 10.1016/j.healun.2020.01.870. Fulltekst i vitenarkiv
• Rolid, Katrine; Andreassen, Arne K.; Yardley, Marianne; Bjørkelund, Elisabeth; Relbo, Anne & Grov, Ingelin [Vis alle 11 forfattere av denne artikkelen] (2020). Benefits of High-Intensity Interval Training in a Young and in an Older De Novo Heart Transplant Recipient- Cases from the HITTS Study. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. 39(4), s. S491–S492. doi: 10.1016/j.healun.2020.01.069. Fulltekst i vitenarkiv
• Lekva, Tove; Gullestad, Lars; Broch, Kaspar; Aukrust, Pål; Andreassen, Arne K. & Ueland, Thor (2020). Distinct patterns of soluble leukocyte activation markers are associated with etiology and outcomes in precapillary pulmonary hypertension. Scientific Reports. 10(1), s. 1–8. doi: 10.1038/s41598-020-75654-w. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Ueland, Thor; Estensen, Mette-Elise; Grindheim, Guro; Bollerslev, Jens; Henriksen, Tore & Aukrust, Pål [Vis alle 9 forfattere av denne artikkelen] (2020). Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies. Journal of Hypertension. ISSN 0263-6352. 38(7), s. 1347–1354. doi: 10.1097/HJH.0000000000002362. Fulltekst i vitenarkiv Vis sammendrag

  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 Ca2+/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.

• Eriksen-Volnes, Torfinn; Westheim, Arne; Gullestad, Lars; Slind, Eva Kjøl & Grundtvig, Morten (2020). β-Blocker Doses and Heart Rate in Patients with Heart Failure: Results from the National Norwegian Heart Failure Registry. Biomedicine Hub. 5(1), s. 9–18. doi: 10.1159/000505474. Fulltekst i vitenarkiv Vis sammendrag

  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 (n = 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 t test for continuous variables and Pearson's χ2 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. Keywords: Chronic heart failure; Comorbidity; Heart rate; Mortality; β-Blocker.

• Massey, Richard J; Diep, Phoi Phoi; Ruud, Ellen; Dirdal, Marta Maria; Kvaslerud, Anette Borger & Brinch, Lorentz [Vis alle 9 forfattere av denne artikkelen] (2020). Left Ventricular Systolic Function in Long-Term Survivors of Allogeneic Hematopoietic Stem Cell Transplantation. JACC: CardioOncology. 2(3), s. 460–471. doi: 10.1016/j.jaccao.2020.06.011. Fulltekst i vitenarkiv Vis sammendrag

  Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a potentially curative therapy for malignant and nonmalignant diseases, is being increasingly used in younger patients. Although allo-HSCT survivors have an established increased risk of cardiovascular disease, there is limited knowledge of the long-term effects on cardiac function in survivors. Objectives The purpose of this study was to describe left ventricular (LV) systolic function in long-term allo-HSCT survivors treated in childhood, adolescence, or early adulthood. Methods Our cross-sectional cohort study included 104 patients (56% women), age 18 ± 10 years at time allo-HSCT with 17 ± 6 years of follow-up. Echocardiography included 2-dimensional (2D) and 3-dimensional (3D) analyses and speckle tracking imaging. In total, 55 healthy control subjects with a similar age, sex, and body mass index were used for comparison. Left ventricular systolic dysfunction (LVSD) was defined as reduced 2D left ventricular ejection fraction (LVEF) of <52% in men and <54% in women, and/or a reduced global longitudinal strain (GLS) of ≥−17%. Multivariable linear regression was used to determine independent predictors of 2D-LVEF and GLS. Results Allo-HSCT survivors had significantly reduced LV systolic function compared with control subjects: 2D-LVEF (55.2 ± 5.8% vs. 59.0 ± 2.9%; p < 0.001), 3D LVEF (54.0 ± 5.1% vs. 57.6 ± 2.7%; p < 0.001), and GLS (−17.5 ± 2.2% vs. −19.8 ± 1.4%; p < 0.001). LVSD was found in 44.2%, of whom 28.3% were symptomatic. Clinical factors independently associated with 2D-LVEF and/or GLS included age, anthracyclines, graft versus host disease (GVHD), heart rate, and hypertension. In the 45% of survivors pre-treated with anthracyclines, the effect of anthracyclines on 2D-LVEF and GLS was dose-dependent. Conclusions LVSD is common in long-term survivors of allo-HSCT treated in their youth. Pre-HSCT therapies with anthracyclines, age, heart rate, hypertension, and graft versus host disease are associated with measures of LV function.

• Bergh, Niklas; Gude, Einar; Bartfay, Sven-Erik; Andreassen, Arne K.; Arora, Satish & Dahlberg, Pia [Vis alle 13 forfattere av denne artikkelen] (2020). Invasive haemodynamics in de novo everolimus vs. calcineurin inhibitor heart transplant recipients. ESC Heart Failure. 7(2), s. 567–576. doi: 10.1002/ehf2.12608. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Nelson, Lærke; Andreassen, Arne K.; Arora, Satish; Andersson, Bert; Gude, Einar & Eiskjær, Hans [Vis alle 10 forfattere av denne artikkelen] (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. Transplant International. ISSN 0934-0874. 33(5), s. 517–528. doi: 10.1111/tri.13577. Fulltekst i vitenarkiv
• Sverre, Elise; Peersen, Kari; Weedon-Fekjær, Harald; Perk, J.; Gjertsen, Erik & Husebye, Einar [Vis alle 10 forfattere av denne artikkelen] (2020). Preventable clinical and psychosocial factors predicted two out of three recurrent cardiovascular events in a coronary population. BMC Cardiovascular Disorders. 20. doi: 10.1186/s12872-020-01368-6. Fulltekst i vitenarkiv Vis sammendrag

  Background The relative importance of lifestyle, medical and psychosocial factors on the risk of recurrent major cardiovascular (CV) events (MACE) in coronary patients’ needs to be identified. The main objective of this study is to estimate the association between potentially preventable factors on MACE in an outpatient coronary population from routine clinical practice. Methods This prospective follow-up study of recurrent MACE, determine the predictive impact of risk factors and a wide range of relevant co-factors recorded at baseline. The baseline study included 1127 consecutive patients 2–36 months after myocardial infarction (MI) and/or revascularization procedure. The primary composite endpoint of recurrent MACE defined as CV death, hospitalization due to MI, revascularization, stroke/transitory ischemic attacks or heart failure was obtained from hospital records. Data were analysed using cox proportional hazard regression, stratified by prior coronary events before the index event. Results During a mean follow-up of 4.2 years from study inclusion (mean time from index event to end of study 5.7 years), 364 MACE occurred in 240 patients (21, 95% confidence interval: 19 to 24%), of which 39 were CV deaths. In multi-adjusted analyses, the strongest predictor of MACE was not taking statins (Relative risk [RR] 2.13), succeeded by physical inactivity (RR 1.73), peripheral artery disease (RR 1.73), chronic kidney failure (RR 1.52), former smoking (RR 1.46) and higher Hospital Anxiety and Depression Scale-Depression subscale score (RR 1.04 per unit increase). Preventable and potentially modifiable factors addressed accounted for 66% (95% confidence interval: 49 to 77%) of the risk for recurrent events. The major contributions were smoking, low physical activity, not taking statins, not participating in cardiac rehabilitation and diabetes. Conclusions Coronary patients were at high risk of recurrent MACE. Potentially preventable clinical and psychosocial factors predicted two out of three MACE, which is why these factors should be targeted in coronary populations. Trial registration Registered at ClinicalTrials.gov: NCT02309255. Registered at December 5th, 2014, registered retrospectively.

• Gustafsson, Finn; Andreassen, Arne K.; Andersson, Bert; Eiskjær, Hans; Rådegran, Göran & Gude, Einar [Vis alle 12 forfattere av denne artikkelen] (2020). Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Long-term Follow-up From the Randomized SCHEDULE Study. Transplantation. ISSN 0041-1337. doi: 10.1097/TP.0000000000002702. Fulltekst i vitenarkiv

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• Birkeland, Kåre Inge; Gullestad, Lars & Aabakken, Lars (2022). Indremedisin I. Fagbokforlaget. ISBN 9788245043365. 479 s. Fulltekst i vitenarkiv
• Birkeland, Kåre Inge; Gullestad, Lars & Aabakken, Lars (2022). Indremedisin I & II, 2. utgave. Fagbokforlaget. ISBN 9788245040968. 1024 s. Fulltekst i vitenarkiv

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• Birkeland, Kåre Inge; Meling, Sondre V.; Alsnes, Ingvild Vatten; Svensson, Emelie; Gullestad, Lars & Jenssen, Trond (2023). Nye internasjonale anbefalingerfor type 2-diabetes – hva gjør vi i Norge? 143(3), s. 1–6. doi: 10.4045/tidsskr.22.0672. Fulltekst i vitenarkiv
• Bardan, Sara; Kvaslerud, Anette Borger; Andresen, Kristoffer; Kløve, Sophie Foss; Edvardsen, Thor & Gullestad, Lars [Vis alle 7 forfattere av denne artikkelen] (2022). Intravenous ferric derisomaltose in iron-deficient patients undergoing transcatheter aortic valve implantation due to severe aortic stenosis: study protocol of the randomised controlled IIISAS trial. BMJ Open. 12(9). doi: 10.1136/bmjopen-2021-059546. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Introduction Iron deficiency is a prevalent comorbidity in patients with severe aortic stenosis and may be associated with procedural and clinical outcomes after transcatheter aortic valve implantation (TAVI). In the Intravenous Iron Supplement for Iron Deficiency in Patients with Severe Aortic Stenosis (IIISAS) trial, we aim to examine whether a single administration of ferric derisomaltose can improve physical capacity after TAVI. Methods and analysis This randomised, double-blind, placebo-controlled trial aims to enrol 150 patients with iron deficiency who are scheduled for TAVI due to severe aortic stenosis. The study drug and matching placebo are administered approximately 3 months prior to TAVI, and the patients are followed for 3 months after TAVI. Inclusion criteria are iron deficiency, defined as serum ferritin<100 µg/L or ferritin between 100 and 300 µg/L in combination with a transferrin saturation<20% and written informed consent. Exclusion criteria include haemoglobin<10 g/dL, red blood cell disorders, end-stage kidney failure, intolerance to ferric derisomaltose, and ongoing infections. The primary endpoint is the baseline-adjusted distance walked on a 6 min walk test (6MWT) 3 months after TAVI. Secondary end points include quality of life, New York Heart Association functional class (NYHA functional class), and skeletal muscle strength. Ethics and dissemination Ethical approval was obtained from the Regional Committee for Medical and Health Research of South-Eastern Norway and The Norwegian Medicines Agency. Enrolment has begun, and results are expected in 2022. The results of the IIISAS trial will be disseminated by presentations at international and national conferences and by publications in peer-reviewed journals.

• Traaen, Gunn Marit; Akre, Harriet; Loennechen, Jan Pål & Gullestad, Lars (2022). Reply to Lalonde et al. American Journal of Respiratory and Critical Care Medicine. ISSN 1073-449X. 205(9), s. 1129–1130. doi: 10.1164/rccm.202112-2738LE. Fulltekst i vitenarkiv
• Aukrust, Pål; Kleveland, Ola & Gullestad, Lars (2021). Targeting IL-6 Trans-Signaling: Amplifying the Benefits of IL-6 Inhibition in Myocardial Infarction. JACC: Basic to Translational Science. ISSN 2452-302X. 6(5), s. 444–446. doi: 10.1016/j.jacbts.2021.01.007. Fulltekst i vitenarkiv
• Broch, Kaspar; Englund, Kristine Victoria Brautaset & Gullestad, Lars (2021). Reply: Safety of intravenous iron in heart transplant patients: Comment to paper by Brautaset Englund et al. The Journal of Heart and Lung Transplantation. ISSN 1053-2498. 40(10), s. 1247–1248. doi: 10.1016/j.healun.2021.07.007. Fulltekst i vitenarkiv
• Peersen, Kari; Sverre, Elise Christine Bjørkholen; Kristiansen, Oscar; Fagerland, Morten; Gullestad, Lars & Otterstad, Jan Erik [Vis alle 8 forfattere av denne artikkelen] (2020). Clinical factors, psychological factors and beliefs about statin use in patients with coronary heart disease and self-perceived muscle side-effects. European Heart Journal. ISSN 0195-668X. 41(Supplement_2). doi: 10.1093/ehjci/ehaa946.3337. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Statin associated muscle symptoms (SAMS) are commonly reported and constitute the principal reason for statin non-adherence and/or discontinuation. Understanding the determinants of SAMS may enhance the clinical management and form the basis of interventions. The association between psychological distress and the beliefs about statin treatment and SAMS have previously not been investigated under randomized, controlled conditions. Purpose To compare clinical and psychological factors among coronary patients with confirmed SAMS and non-SAMS. Methods This pre-planned exploratory study included 71 consecutively recruited patients with self-perceived SAMS enrolled in the MUscle Side-Effect of atorvastatin in coronary patients (MUSE) randomized double-blinded crossover trial. Muscle symptom (pain, weakness, tenderness, stiffness and/or cramps) intensity was registered weekly in a patient diary using a 0 (no symptoms) to 10 (worst imaginable) cm visual-analogue scale (VAS). Confirmed SAMS was predefined as a 25% higher individual mean VAS-scores during 7-weeks treatment with atorvastatin 40 mg/day versus 7-weeks treatment with placebo, and ≥1cm absolute difference. Clinical factors (10 variables), psychological factors (5 variables) and beliefs about medicine (3 variables) were obtained from a questionnaire and a clinical examination at study start. Results Mean age was 63 (SD 9.5) years, 32% were women, and each participant had tried average 1.3 (SD 0.6, range 1 to 3) statins prior to study start. In all, 28% (n=20) had confirmed SAMS and 72% (n=51) had non-SAMS. There were no differences in mean VAS score at study start between the groups (mean VAS score 4.5 vs. 4.7, p=0.20). More patients with confirmed SAMS than non-SAMS (25% vs. 6%, p&lt;0.001) did not use statin treatment at study start, and mean LDL-cholesterol level was borderline higher (2.8 vs. 2.3 mmol/L, p=0.06). Patients with confirmed SAMS had a weaker belief in their statin use compared to patients with non-SAMS (3.1 vs. 3.6, p&lt;0.001) using a 5-category scale from 1 (weak belief) to 5 (strongest belief). There were no differences in the sociodemographic, clinical (pre-existing muscle skeletal disorders, somatic comorbidity, cardiovascular risk factors) or psychological (symptoms of anxiety or depression, type D personality, worry, insomnia) factors explored between patients with confirmed SAMS or with non-SAMS. There were no associations between these factors and increasing VAS scores in continuous analyses among patients with confirmed SAMS and non-SAMS. Conclusions Patients with statin dependent muscle side-effects reported a weaker belief on the necessity to take statins than patients with muscle complaints not caused by the statin. Otherwise, we found no differences in clinical or psychological factors between these populations. The results indicate that these factors do not distinguish patients with and without associated muscle symptoms in clinical practice. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Vestfold Hospital Trust, research grant

• Munkhaugen, John; Sverre, Elise Christine Bjørkholen; Kristiansen, Oscar; Fagerland, Morten; Peersen, Kari & Bergan, Stein [Vis alle 9 forfattere av denne artikkelen] (2020). Drug related metabolites and genetic polymorphisms predict low low-density lipoprotein cholesterol response to atorvastatin treatment in patients with coronary heart disease. European Heart Journal. ISSN 0195-668X. 41(Supplement_2). doi: 10.1093/ehjci/ehaa946.2985. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background There is considerable individual variation in the low-density lipoprotein cholesterol (LDL-C) reduction at all classes and doses of statins. Knowledge of the determinants of individual variation LDL-C response upon statin treatment may pave the way for personalized and optimized statin treatment. Purpose We aimed to determine clinical and drug related predictors of variability of LDL-C response to atorvastatin 40 mg in patients with coronary heart disease. Methods This is an explorative study among 70 patients enrolled in the MUscle Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over trial. Absolute and relative changes in LDL-C after 7 weeks treatment with atorvastatin 40 mg/day and 7 weeks treatment with placebo, were calculated for each patient. Linear regression analyses were applied to investigate the association between clinical (10 variables) and drug related (atorvastatin and/or metabolites, 18 variables) predictors and changes in LDL-C. Results Adherence to allocated treatment was high as confirmed by atorvastatin levels in blood and a mean proportion of days covered of 99% (range 91–100%). Mean reduction in LDL-C on atorvastatin treatment (LDL-C atorvastatin – LDL-C placebo) was 2.1 (SD 0.7, range 0.3 to 3.4) mmol/L. Mean percentage reduction in LDL-C was 51.1 (SD 11.2, range 29 to 60)%, and 37 patients (52.9%) had &lt;50% LDL-C reduction. Genetic polymorphisms in SLCO1B1 or CYP3A (B 0.06, 95% CI 0.01 to 0.12, p=0.026), increasing number of coronary events (B 0.06, 95% CI 0.002 to 0.10, p=0.005), increasing trough concentration of 4-OH atorvastatin lactone (B 0.05, 95% CI 0.01 to 0.08, p=0.005) and increasing trough concentration of 4-OH atorvastatin acid (B 0.05, 95% CI 0.01 to 0.08, p=0.006) were the significant determinants of lower relative change (%) in LDL-C, in adjusted analyses. Age, gender, somatic comorbidity, cardiovascular risk factors, statin dependent muscle side-effects and other clinical and drug related determinants were not associated with changes in LDL-C. Conclusions There is considerable inter-individual variation in the LDL-C response upon treatment with atorvastatin despite confirmed high statin adherence. This is the first study reporting that genetic polymorphisms involved in the metabolism of statins and atorvastatin metabolites predict lower LDL-C response. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Association of Health, Grant/Award

• Slind, Eva Kjøl; Lægran, Marianne; Ingul, Charlotte Ingeborg Björk; Eriksen-Volnes, Torfinn Kirknes; Blindheimsvik, Martin Andre Brevik & Myhre, Peder Langeland [Vis alle 13 forfattere av denne artikkelen] (2022). Norsk hjertesviktregister : Årsrapport 2021 : Med plan for forbedringstiltak. Norsk hjerteviktregister. Fulltekst i vitenarkiv

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