Helge Rørvik Røsjø

• Wimalanathan, Thakshani; Sulkowska, Joanna; Melles, Woldegabriel A; Paus, Michael Fredrik; Skranes, Julia Brox & Berge, Trygve [Show all 11 contributors for this article] (2026). Myocardial fibrosis is associated with worse left ventricular strain and synchrony assessed by novel CMR imaging in the general population: data from the Akershus Cardiac examination 1950 study. The International Journal of Cardiovascular Imaging. ISSN 1569-5794. doi: 10.1007/s10554-026-03746-1. Full text in Research Archive
• Sulkowska, Joanna; Skranes, Julia Brox; Berge, Trygve; Tveit, Arnljot; Røsjø, Helge Rørvik & Lyngbakken, Magnus Nakrem [Show all 9 contributors for this article] (2026). Mechanical signatures of left ventricular ejection fraction and mass index in a community cohort (ACE 1950). The International Journal of Cardiovascular Imaging. ISSN 1569-5794. doi: 10.1007/s10554-026-03697-7. Full text in Research Archive
• Bhatnagar, Rahul; Lippestad, Kristine; Wisløff, Torbjørn; Berg, Angelica Marianne; Klæboe, Lars Gunnar & Høiseth, Arne Didrik [Show all 9 contributors for this article] (2026). Study Design of the Akershus Cardiac Examination (ACE) 4 Study: Pragmatic Randomized Controlled Trial Assessing the Effect of Early Biomarker Measurements and Structured Feedback in Unselected Patients Hospitalized with Tachypnea. Cardiology. ISSN 0008-6312. p. 1–12. doi: 10.1159/000550049. Full text in Research Archive
• Ihle-Hansen, Håkon; Walle-Hansen, Marte; Berge, Trygve; Ihle-Hansen, Hege Beate; Rønningen, Peter Selmer & Omland, Torbjørn [Show all 16 contributors for this article] (2026). Burden of atherosclerosis, cardiovascular risk factors and atrial fibrillation in individuals with covert brain infarcts in late midlife: the Akershus Cardiac Examination 1950 Study. BMJ Open. 16(3). doi: 10.1136/bmjopen-2025-114232. Full text in Research Archive Show summary

  Background Current expert consensus statements generally suggest cardiovascular risk assessment, including atrial fibrillation (AF) screening, on detection of covert brain infarctions (CBIs). However, evidence to guide management of CBI remains limited. In the absence of randomised clinical trials specifically targeting CBI populations, observational studies comparing individuals with and without CBI can provide insights into the prevalence and burden of cardiovascular risk factors. Objectives We aimed to compare the burden of atherosclerosis and cardiovascular risk factors in participants with CBI to those without, and to explore the yield of AF screening in individuals with CBI. Design A prospective population-based birth cohort study including men and women born in 1950 and resident in Akershus County, Norway. Setting The two hospitals serving the population of Akershus county, Norway. Participants Participants included in the Akershus Cardiac Examination (ACE) 1950 study who also underwent a subsequent MRI examination were eligible for this study. Outcome measures Cardiovascular risk assessment was performed at study inclusion (2012–2015). Carotid ultrasound was used to quantify atherosclerosis through a carotid plaque score, and CHA₂DS₂-VA and Systematic COronary Risk Evaluation 2 (SCORE2) scores were calculated to estimate cardiovascular risk. Brain MRI was performed in a randomly selected, blood pressure-stratified subset of participants (2016–2024). CBI was defined as focal lesions consistent with ischaemia in the absence of clinical stroke. Participants with CBI were offered 72-hour ambulatory ECG monitoring for AF detection. Results MRI was performed in 414 of 3706 (11%) participants in the ACE 1950 Study. The mean age at the time of the MRI examination was 70.2±2.3 years, and 165 (41%) were women. CBI was identified in 54 participants (13%), of whom 45 (83%) completed 72-hour ambulatory ECG monitoring. There were no differences in mean carotid plaque score, SCORE2 or CHA₂DS₂-VA score between participants with CBI compared with those with normal MRI findings. AF was detected in one (2%) participant with CBI. Conclusions In this community-based cohort of individuals in late midlife, individuals with CBI did not have an increased cardiovascular risk compared with those without, as indicated by SCORE2, CHA₂DS₂-VA score, age-appropriate carotid plaque burden and a low prevalence of AF. Trial registration number URL: https://www.clinicaltrials.gov . Unique identifier: NCT01555411 .

• Bratholm, Åsmund Olaf; Ihle-Hansen, Håkon; Vigen, Thea; Lyngbakken, Magnus Nakrem; Omland, Torbjørn & Røsjø, Helge Rørvik [Show all 10 contributors for this article] (2026). Association between socioeconomic variables and carotid plaque in middle-aged adults: data from the Akershus Cardiac Examination (ACE) 1950 Study. Open heart. 13(1). doi: 10.1136/openhrt-2025-003865. Full text in Research Archive
• Dypvik, Ragnhild; Fjukstad, Katrine Kveli; Lydersen, Stian; Berge, Trygve; Tveit, Arnljot & Røsjø, Helge Rørvik [Show all 9 contributors for this article] (2025). Associations Between Growth Differentiation Factor 15 and Anxiety and Depression in the General Population: The Akershus Cardiac Examination 1950 Study. Biopsychosocial Science and Medicine. ISSN 2998-8748. 87(2), p. 153–159. doi: 10.1097/psy.0000000000001365. Full text in Research Archive Show summary

  Objective Several studies suggest a bidirectional association between inflammation, and anxiety and depression. Elevated inflammatory cytokines generate and aggravate neuroinflammation, which may play a part in developing psychological symptoms. Growth differentiation factor 15 (GDF-15) is a novel biomarker possibly reflecting fibrosis and inflammation. The aim of the current study was to investigate the associations between levels of GDF-15 and symptoms of anxiety and depression in the general population. Methods We measured GDF-15 in middle-aged persons participating in the Akershus Cardiac Examination 1950 Study. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), with HADS ≥8 denoting significant symptoms. We used multivariable regression analysis to assess the associations between GDF-15 and HADS, adjusting for levels of C-reactive protein (CRP), demographics, and comorbidities. Results A total of 3638 participants had valid assessment of HADS and measurements of GDF-15 and CRP. The mean age was 63.9 (SD 0.65) years, and 48.8% were women. In adjusted models, levels of GDF-15 were associated with the continuous HADS-D score ( β = 0.27, 95% confidence interval [CI] = 0.12 to 0.43) and HADS-D score ≥8 (odds ratio = 1.41, 95% CI = 1.12 to 1.78), but not with the continuous HADS-A score ( β = 0.06, 95% CI = −0.12 to 0.24) or HADS-A score ≥8 (odds ratio = 1.06, 95% CI = 0.88 to 1.27). Conclusions Levels of GDF-15 are independently associated with symptoms of depression in the general population. Our results reinforce the notion that inflammation may be a contributing factor for the development of clinical depression. Registration ClinicalTrials.gov identifier NCT01555411 (Akershus Cardiac Examination [ACE] 1950 Study), https://clinicaltrials.gov/study/NCT01555411

• Solberg, Magnar Gangås; Berge, Trygve; Rønningen, Peter Selmer; Enger, Steve; Pervez, Mohammad Osman & Orstad, Eivind Bjørkan [Show all 13 contributors for this article] (2025). Long-term impact of blood pressure in women and men in their early 40s on left atrial strain: data from the Akershus Cardiac Examination (ACE) 1950 Study. Open heart. 12(2). doi: 10.1136/openhrt-2025-003665. Full text in Research Archive Show summary

  Background The life-long exposure of the left heart chambers to systemic blood pressures may be important to changes in left atrial (LA) function with age, but long-term follow-up studies are scarce. We aimed to assess the impact of blood pressure in mid-life on LA function assessed by echocardiographic reservoir (LASr) and contractile (LASct) strain two decades later, in men and women. Methods Echocardiography was performed at ages 62–65 in 3706 participants born in 1950 of the prospective observational Akershus Cardiac Examination (ACE) 1950 Study. Data was linked with blood pressure measurements from the Age 40 Programme, a national health survey performed when the participants were 40–43 years of age. Participants were categorised into three groups representing normal blood pressure, elevated blood pressure and hypertension, based on measurements at ages 40–43. Linear regression models were used to assess associations between blood pressure and echocardiographic LA strain analysis. Results A total of 2399 participants (51.6% women) had available LA strain analysis from the ACE 1950 Study (mean age 63.9±0.6 years) and blood pressure data from the Age 40 Programme (mean age 40.1±0.3 years). At ages 62–65, mean LASr was 35.1±9.2% and LASct was 17.7±5.6%. Adjusted regression models showed a significant association between blood pressure category increase at ages 40–43 and LASct (adjusted β 1.03% (95% CI 0.37% to 1.69%), p=0.002) at ages 62–65, but not with LASr. In women, no associations were evident between blood pressure at ages 40–43 and LA strain two decades later. Conclusions Increased blood pressure in the early 40s was associated with higher LA contractile strain two decades later in men, but not in women.

• Walle-Hansen, Marte; Hagberg, Guri; Myrstad, Marius; Berge, Trygve; Vigen, Thea & Ihle-Hansen, Hege Beate [Show all 14 contributors for this article] (2025). Blood pressure at age 40 and key features of cerebral small vessel disease at age 70: data from the ACE 1950 Study. BMC Cardiovascular Disorders. 25(1). doi: 10.1186/s12872-025-05140-6. Full text in Research Archive Show summary

  Background The separate effects of systolic (SBP) and diastolic blood pressure (DBP) on cerebral small vessel disease (cSVD) development needs elucidation. We investigated the association between SBP and DBP at age 40 and two selected brain magnetic resonance imaging (MRI) features of cSVD (lacunes and white matter hyperintensities [WMHs]) at age 70 in a general Norwegian population cohort. Methods We included individuals from the Akershus Cardiac Examination (ACE) 1950 Study (2012–2015) who had previously participated in the Age 40 Program (1990–1993). A random subset of participants with SBP in the categories of non-elevated (< 120 mmHg), high elevated (130–139 mmHg) or hypertension (≥ 140 mmHg) at age 40 were invited to perform brain MRI for assessment of cSVD (lacunes and WMHs) at age 70 (2016–2024). DBP was categorized as non-elevated (< 70 mmHg), low elevated (70–79 mmHg), high elevated (80–89 mmHg) and hypertension (≥ 90 mmHg). Logistic and ordinal regressions assessed the association between SBP and DBP and lacunes and severity of WMHs (measured with Fazekas scale), adjusting for sex, total cholesterol, smoking, physical activity, diabetes, education, and age at MRI, with non-elevated BP as the reference category. Results A total of 414 participants (167 [40%] women) were included. Participants were 70.2 ± 2.3 years when undergoing brain MRI. Mean Fazekas scale was 1.3 ± 0.8, and 54 (13%) had lacunes. SBP and DPB were not associated with lacunes. DPB of 80–89 mmHg (adjusted OR [95% CI], 1.91 [1.01–3.62]) and ≥ 90 mmHg (2.11 [1.06–4.19]) at age 40 were associated with WMHs. Conclusions Elevated DBP (80–89 mmHg) and diastolic hypertension (> 90 mmHg) at age 40 were associated with WMH burden at age 70, suggesting a long-term association between midlife DBP and cerebrovascular health.

• Rugolo, Ilde; Shen, Xin; Støle, Thea Parsberg; Dahl, Anna Bergan; Manfra, Ornella & Lunde, Marianne [Show all 12 contributors for this article] (2025). Identification of a Small Secretoneurin Derivative That Inhibits CaMKIIδ Activity. Journal of Cellular and Molecular Medicine. ISSN 1582-1838. 29(20). doi: 10.1111/jcmm.70900. Full text in Research Archive Show summary

  ABSTRACT Ventricular arrhythmias, a major cause of sudden cardiac death, are driven by Ca 2+ imbalance in cardiac myocytes, often linked to the overactivation of CaMKIIδ (Ca 2+ /calmodulin‐dependent protein kinase II delta). As such, inhibiting CaMKIIδ represents a promising therapeutic strategy. Based on our previous finding that native secretoneurin (SN) is a weak CaMKIIδ inhibitor, we aimed to develop a more potent derivative of SN to effectively counter aberrant Ca 2+ handling and arrhythmia risk. Various regions of SN were tested for CaMKII binding, identifying the core region as the sequence with the strongest binding capacity. This region was subsequently optimised with two phenylalanine substitutions, resulting in the SN derivative SN‐db‐short. Structural homology modeling and ELISA‐based assays revealed that SN‐db‐short bound both the substrate‐binding (S‐site) region of CaMKIIδ, in addition to the ATP‐binding region, with 8‐fold stronger binding compared to SN. Surface plasmon resonance experiments confirmed that SN‐db‐short exhibited a higher association rate and affinity for CaMKIIδ compared to SN. Consistent with only a partial calmodulin binding motif, SN‐db‐short showed no calmodulin binding, indicating selective CaMKIIδ inhibition. In functional studies, SN‐db‐short inhibited CaMKIIδ‐mediated phosphorylation of ryanodine receptor 2 and appeared more effective than SN in reducing the incidence of Ca 2+ sparks and Ca 2+ waves. SN‐db‐short also more markedly inhibited CaMKIIδ phosphorylation of phospholamban, slowed Ca 2+ reuptake, and reduced the magnitude of Ca 2+ transients during isoproterenol stimulation. SN‐db‐short effectively inhibits CaMKIIδ and significantly counters aberrant Ca 2+ handling in cardiomyocytes. Thus, this optimised peptide holds therapeutic potential for reducing the risk of ventricular arrhythmias.

• Berge, Kristian; Wisløff, Torbjørn; Lippestad, Kristine; Jakobsen, Rune Bruhn; Gjestland, Johanna & Lenvik, Olav [Show all 10 contributors for this article] (2025). Pragmatic, quasi-experimental, pseudo-randomized clinical trial to assess the impact of patient safety monitors on clinical and patient safety outcomes: The Akershus Clinical Trial (ACT) 1. PLOS ONE. 20(10). doi: 10.1371/journal.pone.0335052. Full text in Research Archive Show summary

  Background The Norwegian National Action Plan for Patient Safety and Quality Improvement recommends implementing electronic patient safety monitors (PSM) in Norwegian hospitals. We hypothesized that PSM implementation would reduce hospital length of stay, with secondary endpoints related to clinical and patient safety outcomes. Methods We performed a retrospective single-center, pragmatic, quasi-experimental, pseudo-randomized controlled trial assessing differences in endpoints for patients admitted before (control group: years 2019–2020) and after PSM implementation (intervention group: years 2021–2022) in two orthopedic bays in a Norwegian teaching hospital. To account for temporal changes unrelated to PSM, we assessed the same endpoints for 2019–2020 vs. 2021–2022 in two orthopedic bays that did not implement PSM. Data extraction from the local data warehouse was controlled according to internal standards, and we predefined all statistical analyses. Results The intervention group (n = 2786) and the control group (n = 2610) were evenly distributed for baseline characteristics, including age (median 73 [quartile 1–3 55–83] vs. 72 [55–83] years, p = 0.29), female sex (76.2% vs. 76.4%, p = 0.96), and Charlson Comorbidity Index (p = 0.24). Median hospital length of stay was 4.4 (2.1–7.7) days after implementation of PSM compared to 4.3 (2.0–7.2) days in the control group (p = 0.046 for difference between the groups). Nutritional screening and fall screening within 24 hours were lower in the intervention group compared to the control group, while medical reconciliation during the hospital stay was higher in the intervention group. We found no differences between the groups in 30-day or 1-year readmission or mortality rates. Hospital length of stay was similar in 2021–2022 vs. 2019–2020 for the bays that did not implement PSM. Conclusion The implementation of PSMs in this study did not improve clinical or patient safety outcomes. Hospital length of stay was statistically longer after PSM implementation, although the difference was not clinically relevant.

• Ottesen, Anett Hellebø; Røsjø, Helge Rørvik & Omland, Torbjørn (2025). Secretoneurin as a novel cardiovascular biomarker and potential therapeutic strategy. Expert Review of Cardiovascular Therapy. ISSN 1477-9072. 24(1), p. 21–27. doi: 10.1080/14779072.2025.2604574. Full text in Research Archive Show summary

  Introduction Secretoneurin (SN) is a prognostic biomarker in cardiovascular disease (CVD), and circulating SN concentrations have been associated with clinical outcomes in various cohort of CVDs. SN reflects other cellular pathways than established CV biomarkers, and SN provides incremental prognostic information to established CV risk indices. SN has been found to have several beneficial properties and SN could have potential as a future therapeutic strategy in CVD. Areas covered This review discusses SN as a novel cardiovascular biomarker and a potential therapeutic strategy in cardiovascular medicine. The authors have considered relevant papers identified by PubMed. Expert opinion SN is a prognostic biomarker in CVD, and unraveling the underlying pathophysiology of SN will be important to advance SN as a biomarker and potential future therapy in CVD. The future for SN as a biomarker and therapy is attractive and could be of future clinical relevance.

• Paus, Michael Fredrik; Lyngbakken, Magnus Nakrem; Tveit, Arnljot; Steine, Kjetil; Berge, Trygve & Skranes, Julia Brox [Show all 14 contributors for this article] (2025). Determinants of Cardiac Myosin Binding Protein C in the General Population. Clinical Chemistry. ISSN 0009-9147. 71(4), p. 484–496. doi: 10.1093/clinchem/hvaf013. Full text in Research Archive Show summary

  Background: Cardiac myosin binding protein C (cMyC) is a novel, cardiac-specific biomarker with an early release profile after acute ischemic myocardial injury. Whether cMyC reflects chronic myocardial injury and left ventricular remodelling in the general population is unknown. The aims of the study were to test the hypotheses that cMyC concentrations are associated with cardiovascular risk factors, biomarkers of chronic myocardial injury, and imaging biomarkers of cardiac anatomy, function, and fibrosis. Methods: Circulating cMyC and cardiac troponin I and T concentrations were measured in 3672 individuals from the general population, born in 1950, who underwent echocardiography. One-hundred-ninety-nine participants with measured cMyC completed a cardiovascular magnetic resonance (CMR) examination for assessment of myocardial fibrosis. Results: Circulating cMyC was measurable in 99.6% of study participants and in 99.0% of CMR substudy participants. cMyC was positively associated with left ventricular mass and left atrial volume and inversely associated with renal function and indices of left ventricular systolic and diastolic function. In participants with available late gadolinium enhancement images for the assessment of focal fibrosis (n = 197), cMyC was positively associated with indices of focal myocardial fibrosis. Conclusions: In the general population, circulating cMyC concentrations are associated with cardiovascular risk factors, reflect left ventricular remodelling, including focal myocardial fibrosis, and systolic and diastolic dysfunction independently of traditional risk factors.

• Ihle-Hansen, Håkon; Walle-Hansen, Marte; Hagberg, Guri; Berge, Trygve; Ihle-Hansen, Hege Beate & Rønningen, Peter Selmer [Show all 11 contributors for this article] (2025). Applying the 2024 European Society of Cardiology Guidelines for the management of elevated blood pressure and hypertension to a Norwegian general population cohort from age 40: data from the Akershus Cardiac Examination 1950 study. Heart. ISSN 1355-6037. 111(23), p. 1119–1123. doi: 10.1136/heartjnl-2025-325770. Full text in Research Archive
• Røsjø, Helge Rørvik; Rugolo, Ilde; Berg, Angelica Marianne; Faaren, Arne L; Frantzen, Frank & Christensen, Geir [Show all 11 contributors for this article] (2025). Secretoneurin Concentrations Measured with a High-Throughput Assay and Clinical Outcomes in Patients Hospitalized with Acute Dyspnea: Data from the Akershus Cardiac Examination 2 Study. The Journal of Applied Laboratory Medicine (JALM). ISSN 2576-9456. 10(3), p. 691–703. doi: 10.1093/jalm/jfaf011. Full text in Research Archive Show summary

  Background High-throughput assays are required for novel biomarkers to have clinical potential. Secretoneurin (SN) is a candidate biomarker, and the performance of a new high-throughput SN assay is not known. Methods We measured SN concentrations with a prototype chemiluminescent immunoassay (CLIA) in 299 patients hospitalized with acute dyspnea. We compared the results with a CE-marked SN enzyme linked immunosorbent assay (ELISA). We adjudicated the cause of dyspnea as heart failure (HF) or non-HF, and we obtained information on all-cause mortality during follow-up. Results SN concentrations measured with CLIA and ELISA were closely correlated: rho = 0.81, P < 0.001. SN CLIA concentrations were higher in HF patients (n = 129) compared to patients with non-HF-related dyspnea (n = 170): median 51 (quartile 1–3 40–69) vs 41 (32–54) pmol/L, P < 0.001. The area under the curve (AUC) of SN CLIA to diagnose HF was 0.64 (95% CI, 0.58–0.71) and the AUC of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 0.85 (0.81–0.89). During median 818 days follow-up, 110 patients died (37%). There was a nonlinear association between SN CLIA concentrations and mortality with optimal cutpoint 53 pmol/L. SN CLIA concentrations >53 pmol/L were associated with mortality after adjusting for clinical variables and NT-proBNP and cardiac troponin T concentrations: hazard ratio 1.7 (95% CI, 1.1–2.7), AUC 0.67 (0.61–0.74). We found similar results for SN ELISA for diagnosis and prognosis with AUC 0.63 (0.57–0.70) for the prediction of mortality. Conclusion The high-throughput SN CLIA correlates with the SN ELISA and provides independent prognostic information over established biomarkers in patients with acute dyspnea.

• Liboriussen, Caroline; Nygaard, Louis; Lyngbakken, Magnus Nakrem; Bakkan, Sara Marie Engelsvold; Jensen, Jens Dam & Glerup, Rie Io [Show all 9 contributors for this article] (2025). Secretoneurin is not associated with cardiovascular events or mortality in patients treated with hemodialysis: A prospective multicenter cohort study. Clinical Biochemistry. ISSN 0009-9120. 136. doi: 10.1016/j.clinbiochem.2025.110899. Full text in Research Archive Show summary

  Introduction Secretoneurin (SN) is a novel cardiac biomarker with an upper reference limit of ∼60 pmol/L in healthy individuals. High SN concentrations have been associated with an increased risk of mortality in various cardiac diseases. We investigated the association between SN and the risk of cardiovascular (CV) events and all-cause mortality in patients treated with maintenance hemodialysis (HD). Materials and Methods Prospective multicenter cohort study with five years of follow-up. Serum SN (pmol/L) was measured at baseline. Outcomes were CV events (composite outcome) and all-cause mortality. The population was divided into tertiles according to SN concentrations: tertile 1 < 110.7 pmol/L, tertile 2 110.7–143 pmol/L, and tertile 3 > 143 pmol/L. The association between SN tertiles and outcomes was examined using Cox regression analysis. Results The study included 336 patients treated with HD. Median SN concentration was 126 (100–153) pmol/L. During a median follow-up of 5.05 (5.02–5.07) years, 42 % had a CV event and 60 % died. Despite overall high SN concentrations, neither SN tertile 2 nor SN tertile 3 was associated with the risk of CV events (HRtertile2 1.27 (95 % CI 0.84–1.93) and HRtertile3 1.20 (95 % CI 0.76–1.90)) or all-cause mortality (HRtertile2 0.84 (95 % CI 0.60–1.18) and HRtertile3 0.90 (95 % CI 0.62–1.31)), when compared to tertile 1. Conclusions Patients treated with HD have high SN concentrations; however, SN was not associated with CV events or all-cause mortality after five years of follow-up. High concentrations of SN, possibly explained by both impaired renal clearance and a high prevalence of cardiomyopathy, may limit its prognostic relevance in patients treated with maintenance HD.

• Omland, Torbjørn; Røsjø, Helge Rørvik; Wisløff, Torbjørn; Bernard, Michael L.; Hiltbold, A.Elise & Khatib, Sammy [Show all 9 contributors for this article] (2025). Serial secretoneurin measurement and risk of ventricular arrhythmias and death in patients with left ventricular systolic dysfunction. Clinical Biochemistry. ISSN 0009-9120. 135. doi: 10.1016/j.clinbiochem.2024.110868. Full text in Research Archive Show summary

  Background Secretoneurin, a member of the granin protein family, is associated with the risk of mortality in patients with acute and chronic heart failure. Secretoneurin may play an important role in cardiomyocyte calcium handling, suggesting that it may influence cardiac arrhythmia risk. We hypothesized that baseline and serial measurements of circulating secretoneurin are associated with the risk of incident ventricular tachyarrhythmias (VA) and death, and that serial measurement would provide prognostic information beyond baseline values. Methods We measured circulating secretoneurin concentrations in blood samples obtained at 3-month intervals for one year in a prospectively enrolled cohort of ambulatory patients with left ventricular ejection fraction (LVEF) ≤ 35 % and a primary-prevention implanted cardioverter defibrillator (ICD). Associations between secretoneurin modeled as a time-dependent variable and the incidences of VA and death were assessed. Results 154 patients (66 ± 14 years, LVEF 23 ± 8 %) were included in the analysis. During one-year follow-up, 26 (17 %) patients experienced VA, and 16 (10 %) died. Adjusting for age, sex, eGFR, and LVEF, baseline secretoneurin concentration was associated with the risk of death (hazard ratio (HR) per 10 pmol/L increase: 1.14 (95 % CI: 1.02–1.27), p = 0.020) but not VA (HR: 0.98 (0.81–1.19), p = 0.856). Using serial measurements at 3-month intervals, time-varying secretoneurin was associated with a similarly higher risk of death (HR: 1.14 (1.02–1.27), p = 0.017) but not of VA (HR: 0.97 (0.81–1.17), p = 0.776). Conclusion In stable ambulatory patients with reduced LV systolic function and a primary prevention indication for ICD, secretoneurin concentration was associated with the risk of death but not ventricular tachyarrhythmia.

• Bhatnagar, Rahul; Berge, Kristian; Høiseth, Arne Didrik; Omland, Torbjørn; Lyngbakken, Magnus Nakrem & Røsjø, Helge Rørvik (2024). Associations between Chest Pain, Diagnosis, and Clinical Outcome in Patients Hospitalized with Acute Dyspnea: Data from the ACE 2 Study. Cardiology. ISSN 0008-6312. 150(3), p. 242–242. doi: 10.1159/000541897. Full text in Research Archive Show summary

  <p>Introduction: Patients hospitalized due to dyspnea sometimes also report concomitant chest pain. Whether co-existing chest pain in patients with acute dyspnea associates with specific diagnosis and clinical outcome is not known. Method: We included 313 patients admitted to Akershus University Hospital with acute dyspnea and asked the patients directly on hospital admission whether they had experienced chest pain during the last 24 h. We examined the associations between chest pain and (1) diagnosis of the index hospitalization and (2) clinical outcome during follow-up. The diagnosis for the index hospitalization was adjudicated as acute heart failure (HF) or non-HF etiology of acute dyspnea by two experts working independently. Non-HF patients were further sub-grouped into chronic obstructive pulmonary disease (COPD) or non-COPD etiology. Results: In total, 143 patients were admitted with acute HF (46% of the population), 83 patients with COPD (26% of the population), and 87 patients with non-HF, non-COPD-related dyspnea (28% of the population). Ninety-six patients (31%) with acute dyspnea reported chest pain during the last 24 h prior to hospital admission. The prevalence of chest pain was not statistically different for patients who were hospitalized with acute HF (n = 42, 44%), acute exacerbation of COPD (n = 22, 23%), or non-HF, non-COPD-related dyspnea (n = 32, 33%), p > 0.05 for all comparisons between groups. During median of 823 days follow-up, 114 patients died (36%). Patients with dyspnea and concomitant chest pain did not have different outcome compared to patients with dyspnea and no chest pain (log-rank test: p = 0.09). Chest pain prior to admission was neither associated with all-cause mortality in any of the adjudicated diagnosis groups. Conclusions: Chest pain was reported in 31% of patients hospitalized with acute dyspnea but the prevalence did not differ according to adjudicated diagnosis. Patients with dyspnea and chest pain did not have worse outcome compared to patients with dyspnea and no chest pain. </p>

• Koechlin, Luca; Boeddinghaus, Jasper; Lopez-Ayala, Pedro; Reber, Cornelia; Nestelberger, Thomas & Wildi, Karin [Show all 46 contributors for this article] (2024). Clinical and Analytical Performance of a Novel Point-of-Care High-Sensitivity Cardiac Troponin I Assay. Journal of the American College of Cardiology. ISSN 0735-1097. 84(8), p. 726–740. doi: 10.1016/j.jacc.2024.05.056. Full text in Research Archive
• Bhatnagar, Rahul; Berge, Kristian; Høiseth, Arne Didrik; Omland, Torbjørn; Lyngbakken, Magnus Nakrem & Røsjø, Helge Rørvik (2024). Associations between Chest Pain, Diagnosis, and Clinical Outcome in Patients Hospitalized with Acute Dyspnea: Data from the ACE 2 Study. Cardiology. ISSN 0008-6312. doi: 10.1159/000541897. Full text in Research Archive Show summary

  Introduction: Patients hospitalized due to dyspnea sometimes also report concomitant chest pain. Whether co-existing chest pain in patients with acute dyspnea associates with specific diagnosis and clinical outcome is not known. Method: We included 313 patients admitted to Akershus University Hospital with acute dyspnea and asked the patients directly on hospital admission whether they had experienced chest pain during the last 24 h. We examined the associations between chest pain and (1) diagnosis of the index hospitalization and (2) clinical outcome during follow-up. The diagnosis for the index hospitalization was adjudicated as acute heart failure (HF) or non-HF etiology of acute dyspnea by two experts working independently. Non-HF patients were further sub-grouped into chronic obstructive pulmonary disease (COPD) or non-COPD etiology. Results: In total, 143 patients were admitted with acute HF (46% of the population), 83 patients with COPD (26% of the population), and 87 patients with non-HF, non-COPD-related dyspnea (28% of the population). Ninety-six patients (31%) with acute dyspnea reported chest pain during the last 24 h prior to hospital admission. The prevalence of chest pain was not statistically different for patients who were hospitalized with acute HF (n = 42, 44%), acute exacerbation of COPD (n = 22, 23%), or non-HF, non-COPD-related dyspnea (n = 32, 33%), p > 0.05 for all comparisons between groups. During median of 823 days follow-up, 114 patients died (36%). Patients with dyspnea and concomitant chest pain did not have different outcome compared to patients with dyspnea and no chest pain (log-rank test: p = 0.09). Chest pain prior to admission was neither associated with all-cause mortality in any of the adjudicated diagnosis groups. Conclusions: Chest pain was reported in 31% of patients hospitalized with acute dyspnea but the prevalence did not differ according to adjudicated diagnosis. Patients with dyspnea and chest pain did not have worse outcome compared to patients with dyspnea and no chest pain.

• Wimalanathan, Thakshani; Paus, Michael Fredrik; Skranes, Julia Brox; Berge, Trygve; Tveit, Arnljot & Røsjø, Helge Rørvik [Show all 9 contributors for this article] (2024). Associations between Growth Differentiation Factor 15, Cardiac Troponin T, and N-terminal pro-B-type Natriuretic Peptide, and Future Myocardial Fibrosis Assessed by Cardiac Magnetic Resonance Imaging: Data from the Akershus Cardiac Examination 1950 Study. The Journal of Applied Laboratory Medicine (JALM). ISSN 2576-9456. 10(2), p. 392–405. doi: 10.1093/jalm/jfae145. Full text in Research Archive Show summary

  Background Myocardial fibrosis is associated with a poor outcome for patients with cardiovascular disease (CVD). Growth differentiation factor 15 (GDF-15) concentrations predict the risk of death in patients with CVD, but the underlying pathophysiological mechanisms are poorly understood. We aimed to assess the associations between biomarkers of cellular stress and inflammation (GDF-15), cardiac injury (cardiac troponin T [cTnT]), and stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), and subsequent focal and diffuse myocardial fibrosis assessed by cardiac magnetic resonance (CMR) imaging. Methods We measured GDF-15, cTnT, and NT-proBNP in 200 study participants without known coronary artery disease or renal dysfunction from the population-based Akershus Cardiac Examination 1950 Study at baseline in 2012 to 2015. Focal myocardial scars and diffuse fibrosis were assessed by late gadolinium enhancement imaging and septal extracellular volume fraction (ECV) by CMR 4 to 7 years later. The relationships between cardiac biomarkers and CMR parameters were assessed by logistic regression analysis adjusted for common cardiovascular risk factors. Results The median age was 63.9 (interquartile range 63.4–64.5) years and 49% were women. GDF-15 (adjusted odds ratio [aOR] 4.40, 95% CI 1.09–17.72) and cTnT (aOR 1.59, 95% CI 1.01–2.50) were associated with nonischemic scars in the fully adjusted model. cTnT (aOR 2.45, 95% CI 1.41–4.25) and NT-proBNP (aOR 3.12, 95% CI 1.55–6.28) were associated with ischemic scars. None of the biomarkers were significantly associated with elevated ECV. Conclusions In a general population cohort, GDF-15, an emerging biomarker of cellular stress and inflammation, associates with nonischemic scars. Biomarkers of myocardial injury and stretch associate with ischemic scars, while no biomarker was associated with diffuse fibrosis as assessed by CMR.

• Sulkowska, Joanna; Melles, Woldegabriel A; Skranes, Julia Brox; Berge, Trygve; Tveit, Arnljot & Røsjø, Helge Rørvik [Show all 9 contributors for this article] (2024). Cardiac troponin T associates with left ventricular function and synchrony assessed by CMR in the general population: results from the Akershus Cardiac Examination 1950 Study. European Heart Journal – Imaging Methods and Practice (EHJ-IMP). 2(3). doi: 10.1093/ehjimp/qyae078. Full text in Research Archive Show summary

  Background and aim Cardiac troponin T (cTnT) is a blood biomarker of myocardial injury that is associated with future adverse cardiovascular events in the general population. Left ventricular (LV) global longitudinal strain (GLS) and mechanical dispersion (MD) are metrics of systolic function and synchrony that can be obtained from cardiac imaging. Studies suggest an association between cTnT and echocardiographically assessed GLS and MD, but it is unknown whether cTnT relates to these metrics when assessed by cardiac magnetic resonance (CMR). We hypothesized that cTnT associates with GLS and with MD assessed by CMR feature tracking (CMR-FT) in the general population. Methods and results cTnT and CMR-FT measurements were performed in 186 community dwellers from the Akershus Cardiac Examination 1950 Study. The participants’ age ranged from 68 to 70 years. Median cTnT concentration was 7.0 ng/L (interquartile interval 5.0–12.6 ng/L), median absolute value of GLS was 17.3% (interquartile interval 15.7–18.8%), and median MD was 80.7 milliseconds (interquartile interval 61.8–105.0 milliseconds). In multivariable linear regression models adjusted for common clinical risk factors of cardiovascular disease, with GLS and MD as outcome and cTnT as the predictor variable of interest, log10 transformed cTnT was significantly associated with both absolute GLS [β-coefficient −1.65, confidence interval (−2.84, −0.46)] and MD [β-coefficient 28.56, confidence interval (12.14, 44.92)]. Conclusion In older adults from the general population, higher cTnT concentrations are associated with worse systolic function and synchrony assessed by CMR-FT LV GLS and MD, adding information about myocardial function to traditional risk factors.

• Røsjø, Helge Rørvik; Solberg, Ole Geir; Aaberge, Lars; Bosse, Gerhard; Omland, Torbjørn & Stavem, Knut [Show all 7 contributors for this article] (2024). Trans-Cardiac Gradient of Secretoneurin in Patients with Takotsubo Syndrome. Cardiology. ISSN 0008-6312. 149(5), p. 466–471. doi: 10.1159/000539094. Full text in Research Archive
• Ihle-Hansen, Hege Beate; Einvik, Gunnar; Hagberg, Guri; Thommessen, Bente; Rønning, Ole Morten & Vigen, Thea [Show all 11 contributors for this article] (2024). Sleep Duration and Cognitive Function: The Akershus Cardiac Examination 1950 Study. Dementia and Geriatric Cognitive Disorders. ISSN 1420-8008. 53(6), p. 338–344. doi: 10.1159/000540273. Full text in Research Archive
• Young, Juliet; Lyngbakken, Magnus Nakrem; Hveem, Kristian; Røsjø, Helge Rørvik & Omland, Torbjørn (2024). Systolic Blood Pressure, Diastolic Blood Pressure and Pulse Pressure and the Risk of Subclinical Myocardial Injury: The HUNT Study. Journal of the American Heart Association (JAHA). 13(9). doi: 10.1161/JAHA.123.031107. Full text in Research Archive Show summary

  Background: Subclinical myocardial injury expressed as higher cardiac troponin concentrations may represent an important intermediary between hypertension and the risk of cardiovascular disease. The study aimed to assess the relative strength of associations between systolic blood pressure (BP), diastolic BP, and pulse pressure, and subclinical myocardial injury, and how change in BP variables over time associates with subclinical myocardial injury. Methods and Results: cTnl (cardiac troponin I) was measured in 32 968 participants of the fourth wave of the population‐based cohort HUNT4 (Trøndelag Health Study) without a history of cardiovascular disease. An additional longitudinal analysis included participants from HUNT4 with BP measurements from HUNT3 (n=18 681). Associations between BP variables and cTnI concentrations were assessed by linear and logistic regression analyses. The median cTnI concentration was 1.6 ng/L (25th–75th percentiles, 0.6–3.1 ng/L), median age was 52 years (39.1–65.6 years), and 57% were female subjects. Cross‐sectionally, only systolic BP categories ≥130 mm Hg associated with higher cTnI concentrations, compared with a reference systolic BP of <110 mm Hg. All categories of diastolic BP and pulse pressure were positively associated with higher cTnI concentrations when diastolic BP 70 to 79 mm Hg and pulse pressure <40 mm Hg were used as references, respectively. When comparing systolic BP, diastolic BP, and pulse pressure as continuous variables, cross‐sectionally, pulse pressure most strongly associated with cTnI concentrations (P for all comparisons <0.001), whereas longitudinally, change in diastolic BP was most strongly associated with cTnI concentrations (P for all comparisons <0.05). Conclusions: Subjects with high pulse pressure and longitudinal increase in diastolic BP are at higher risk for subclinical myocardial injury.

• Mecinaj, Albulena; Gulati, Geeta; Ree, Anne Hansen; Gravdehaug, Berit; Røsjø, Helge Rørvik & Steine, Kjetil [Show all 10 contributors for this article] (2024). Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction. JACC: CardioOncology. 6(1), p. 83–95. doi: 10.1016/j.jaccao.2023.10.008. Full text in Research Archive Show summary

  Background The impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. Objectives The aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. Methods The cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. Results The cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. Conclusions Mild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)

• Aakre, Kristin Moberg; Lyngbakken, Magnus Nakrem; Faaren, Arne L.; Røsjø, Helge Rørvik; Dalen, Håvard & Omland, Torbjørn (2024). Reference intervals of circulating secretoneurin concentrations determined in a large cohort of community dwellers: the HUNT study. Clinical Chemistry and Laboratory Medicine. ISSN 1434-6621. 62(10), p. 2030–2036. doi: 10.1515/cclm-2024-0154. Full text in Research Archive Show summary

  Objectives Secretoneurin (SN) is a novel cardiac biomarker that associates with the risk of mortality and dysfunctional cardiomyocyte Ca2+ handling in heart failure patients. Reference intervals for SN are unknown. Methods SN was measured with a CE-marked ELISA in healthy community dwellers from the fourth wave of the Trøndelag Health Study (HUNT4) conducted in 2017–2019. The common, sex and age specific 90th, 95th, 97.5th and 99th percentiles were calculated using the non-parametric method and outlier exclusion according to the Reed test. The applicability of sex and age specific reference intervals were investigated using Harris and Boyd test. We also estimated the percentiles in a subset with normal findings on echocardiographic screening. Results The total cohort included 887 persons (56.4 % women). After echocardiographic screening 122 persons were excluded, leaving a total of 765 persons (57.8 % women). The 97.5th percentile (95 % CI in brackets) of SN was 59.7 (57.5–62.1) pmol/L in the total population and 58.6 (57.1–62.1) pmol/L after echocardiography screening. In general, slightly higher percentiles were found in women and elderly participants, but less than 4 % in these subgroups had concentrations deviating from the common 97.5th percentile. Low BMI or eGFR was also associated with higher concentrations of SN. Conclusions Upper reference limits for SN were similar amongst healthy adult community dwellers regardless of prescreening including cardiac echocardiography or not. Women and elderly showed higher concentrations of SN, but the differences were not sufficiently large to justify age and sex stratified upper reference limits

• Walle-Hansen, Marte; Hagberg, Guri; Myrstad, Marius; Berge, Trygve; Vigen, Thea & Ihle-Hansen, Hege Beate [Show all 13 contributors for this article] (2024). Systolic blood pressure at age 40 and 30-year stroke risk in men and women. Open heart. 11(2). doi: 10.1136/openhrt-2024-002805. Full text in Research Archive Show summary

  Background American and European guidelines define hypertension differently and are sex agnostic. Our aim was to assess the impact of different hypertension thresholds at the age of 40 on 30-year stroke risk and to examine sex differences. Methods We included 2608 stroke-free individuals from the Akershus Cardiac Examination 1950 Study, a Norwegian regional study conducted in 2012–2015 of the 1950 birth cohort, who had previously participated in the Age 40 Program, a nationwide health examination study conducted in 1990–1993. We categorised participants by systolic blood pressure (SBP) at age 40 (<120 mm Hg (reference), 120–129 mm Hg, 130–139 mm Hg and ≥140 mm Hg) and compared stroke risk using Cox proportional hazard regressions adjusted for age, sex, smoking, cholesterol, physical activity, obesity and education. Fatal and non-fatal strokes were obtained from the Norwegian Cardiovascular Disease Registry from 1 January 2012 to 31 December 2020, in addition to self-reported strokes. Results The mean age was 40.1±0.3 years (50.4% women) and mean SBP was 128.3±13.5 mm Hg (mean±SD). Stroke occurred in 115 (4.4%) individuals (32 (28%) women and 83 (72%) men) during 29.4±2.9 years of follow-up. SBP between 130 and 139 mm Hg was not associated with stroke (adjusted HR 1.71, 95% CI 0.87 to 3.36) while SBP ≥140 mm Hg was associated with increased stroke risk (adjusted HR 3.11, 95% CI 1.62 to 6.00). The adjusted HR of stroke was 4.32 (95% CI 1.66 to 11.26) for women and 2.66 (95% CI 1.03 to 6.89) for men, with non-significant sex interactions. Conclusions SBP ≥140 mm Hg was significantly associated with 30-year stroke risk in both sexes. A small subgroup of women had SBP ≥140 mm Hg and systolic hypertension was a strong risk factor for stroke in these women.

• Solberg, Magnar Gangås; Enger, Steve; Berge, Trygve; Rønningen, Peter Selmer; Aagaard, Erika Nerdrum & Pervez, Mohammad Osman [Show all 12 contributors for this article] (2024). Left atrial function in middle-aged men and women with and without paroxysmal atrial fibrillation: Data from the Akershus Cardiac Examination (ACE) 1950 study. Echocardiography. ISSN 0742-2822. 41(6). doi: 10.1111/echo.15852. Full text in Research Archive Show summary

  Purpose To assess left atrial (LA) function in individuals with known paroxysmal atrial fibrillation (AF) compared with healthy and nonhealthy individuals without atrial fibrillation. Methods The Akershus Cardiac Examination 1950 Study included 3,706 individuals all born in 1950. LA strain assessment of reservoir (LASr), conduit (LAScd) and contractile (LASct) functions were performed in all participants by investigators blinded to clinical data. Participants with cardiovascular disease, obesity, diabetes, pulmonary or renal disease were defined as nonhealthy, and those without as healthy. Patients with paroxysmal AF were identified through medical history and ECG documentation. Results LA strain assessment was feasible in 3,229 (87%) of the participants (50% women). The healthy group (n = 758) had significantly higher LASr and LAScd than the nonhealthy (n = 2,376), but LASct was similar between the groups. Participants with paroxysmal AF had significantly lower values of all strain parameters than the other groups. Multivariable logistic regression showed a significantly reduced probability of having AF per standard deviation increase in LASr and LASct. A nonlinear restricted cubic spline model fitted better with the association of LASr with paroxysmal AF than the linear model, and LA strain values below the population mean associated with an increased probability of having AF, but for values above the population mean no such association was present. Conclusion Compared to participants without AF, those with known paroxysmal AF had significantly lower values of all LA strain parameters during sinus rhythm. Lower values of LA strain were associated with a significantly increased probability of having AF.

• Sourour, Nur; Riveland, Egil Aarstad; Næsgaard, Patrycja; Kjekshus, Harald; Larsen, Alf Inge & Røsjø, Helge Rørvik [Show all 8 contributors for this article] (2024). Associations Between Biomarkers of Myocardial Injury and Systemic Inflammation and Risk of Incident Ventricular Arrhythmia. JACC: Clinical Electrophysiology. ISSN 2405-500X. 10(9), p. 2021–2032. doi: 10.1016/j.jacep.2024.04.017. Full text in Research Archive
• Røsjø, Helge Rørvik; Meessen, Jennifer; Ottesen, Anett Hellebø; Latini, Roberto & Omland, Torbjørn (2023). Prognostic value of secretoneurin in chronic heart failure. Data from the GISSI-Heart Failure trial. Clinical Biochemistry. ISSN 0009-9120. 118. doi: 10.1016/j.clinbiochem.2023.110595. Full text in Research Archive Show summary

  Background Circulating secretoneurin (SN) concentrations have been found to provide prognostic information in patients with acute heart failure. We wanted to assess whether SN would improve prognostication also in patients with chronic heart failure (HF) in a large multicenter trial. Methods We measured plasma SN concentrations at randomization (n = 1224) and after 3 months (n = 1103) in patients with chronic, stable HF from the GISSI-HF study. The co-primary endpoints were (1) time to death or (2) admission to hospital for cardiovascular reasons. Results Mean age was 67 years and 80% were male. Median (quartile 1–3) SN concentrations were 42.6 (35.0–62.8) pmol/L on randomization and 42.0 (34.5–53.1) pmol/L after 3 months, which are higher than SN concentrations in healthy subjects. Higher SN concentrations at randomization were associated with lower body-mass index (BMI), lower systolic blood pressure, lower estimated glomerular filtration rate (eGFR), higher B-type natriuretic peptide (BNP) concentrations, and diagnosis of chronic obstructive pulmonary disease. During median follow-up of 3.9 years, 344 patients (27.0%) died. After adjusting for age, sex, left ventricular ejection fraction, BMI, functional class, ischemic etiology, heart rate, blood pressure, eGFR, bilirubin, comorbidities, and BNP concentrations, logarithmically transformed SN concentrations on randomization were associated with mortality (HR 2.60 (95% CI 1.01–6.70), p = 0.047). SN concentrations were also associated with admission to hospital for cardiovascular reasons, but the association was attenuated and no longer significant in multivariable analysis. Conclusion Plasma SN concentrations provided incremental prognostic information to established risk indices and biomarkers in a large cohort of chronic HF patients.

• Sæther, Julie Caroline; Vesterbekkmo, Elisabeth Kleivhaug; Taraldsen, Maria Dalen; Gigante, Bruna; Follestad, Turid & Røsjø, Helge Rørvik [Show all 10 contributors for this article] (2023). Associations between circulating microRNAs and lipid-rich coronary plaques measured with near-infrared spectroscopy. Scientific Reports. 13(1). doi: 10.1038/s41598-023-34642-6. Full text in Research Archive Show summary

  Lipid-rich coronary atherosclerotic plaques often cause myocardial infarction (MI), and circulating biomarkers that reflect lipid content may predict risk of MI. We investigated the association between circulating microRNAs (miRs) are lipid-rich coronary plaques in 47 statin-treated patients (44 males) with stable coronary artery disease undergoing percutaneous coronary intervention. We assessed lipid content in non-culprit coronary artery lesions with near-infrared spectroscopy and selected the 4 mm segment with the highest measured lipid core burden index (maxLCBI4mm). Lipid-rich plaques were predefined as a lesion with maxLCBI4mm ≥ 324.7. We analyzed 177 circulating miRs with quantitative polymerase chain reaction in plasma samples. The associations between miRs and lipid-rich plaques were analyzed with elastic net. miR-133b was the miR most strongly associated with lipid-rich coronary plaques, with an estimated 18% increase in odds of lipid-rich plaques per unit increase in miR-133b. Assessing the uncertainty by bootstrapping, miR-133b was present in 82.6% of the resampled dataset. Inclusion of established cardiovascular risk factors did not attenuate the association. No evidence was found for an association between the other analyzed miRs and lipid-rich coronary plaques. Even though the evidence for an association was modest, miR-133b could be a potential biomarker of vulnerable coronary plaques and risk of future MI. However, the prognostic value and clinical relevance of miR-133b needs to be assessed in larger cohorts.

• Bhatnagar, Rahul; Berge, Kristian; Røysland, Ragnhild; Høiseth, Arne Didrik; Brynildsen, Jon & Christensen, Geir [Show all 9 contributors for this article] (2023). Cardiac Troponin T and NT-proBNP for Prediction of 30-Day Readmission or Death in Patients with Acute Dyspnea: Data from the Akershus Cardiac Examination 2 Study. Cardiology. ISSN 0008-6312. 148(6), p. 506–516. doi: 10.1159/000533266. Full text in Research Archive Show summary

  Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) measurements are recommended in patients with acute dyspnea. We aimed to assess the prognostic merit of cTnT compared to NT-proBNP for 30-day readmission or death in patients hospitalized with acute dyspnea. Methods: We measured cTnT and NT-proBNP within 24 h in 314 patients hospitalized with acute dyspnea and adjudicated the cause of the index admission. Time to first event of readmission or death ≤30 days after hospital discharge was recorded, and cTnT and NT-proBNP measurements were compared head-to-head. Results: Patients who died (12/314) or were readmitted (71/314) within 30 days had higher cTnT concentrations (median: 32.6, Q1–Q3: 18.4–74.2 ng/L vs. median: 19.4, Q1–Q3: 8.4–36.1 ng/L; p for comparison &amp;lt;0.001) and NT-proBNP concentrations (median: 1,753.6, Q1–Q3: 464.2–6,862.0 ng/L vs. median 984, Q1–Q3 201–3,600 ng/L; for comparison p = 0.027) compared to patients who survived and were not readmitted. cTnT concentrations were associated with readmission or death within 30 days after discharge both in the total cohort (adjusted hazard ratio [aHR]: 1.64, 95% confidence interval [CI]: 1.30–2.05) and in patients with heart failure (HF) (aHR: 1.58, 95% CI: 1.14–2.18). In contrast, NT-proBNP concentrations were not associated with short-term events, neither in the total cohort (aHR: 1.10, 95% CI: 0.94–1.30) nor in patients with adjudicated HF (aHR: 1.06, 95% CI: 0.80–1.40). Conclusion: cTnT concentrations are associated with 30-day readmission or death in patients hospitalized with acute dyspnea, as well as in patients adjudicated HF.

• Ihle-Hansen, Håkon; Vigen, Thea; Berge, Trygve; Walle-Hansen, Marte; Hagberg, Guri & Ihle-Hansen, Hege Beathe [Show all 12 contributors for this article] (2023). Carotid Plaque Score for Stroke and Cardiovascular Risk Prediction in a Middle-Aged Cohort From the General Population. Journal of the American Heart Association (JAHA). 12(17), p. 1–10. doi: 10.1161/JAHA.123.030739. Full text in Research Archive Show summary

  Background We aimed to explore the predictive value of the carotid plaque score, compared with the Systematic Coronary Risk Evaluation 2 (SCORE2) risk prediction algorithm, on incident ischemic stroke and major adverse cardiovascular events and establish a prognostic cutoff of the carotid plaque score. Methods and Results In the prospective ACE 1950 (Akershus Cardiac Examination 1950 study), carotid plaque score was calculated with ultrasonography at inclusion in 2012 to 2015. The largest plaque diameter in each extracranial segment of the carotid artery on both sides was scored from 0 to 3 points. The sum of points in all segments provided the carotid plaque score. The cohort was followed up by linkage to national registries for incident ischemic stroke and major adverse cardiovascular events (nonfatal ischemic stroke, nonfatal myocardial infarction, and cardiovascular death) throughout 2020. Carotid plaque score was available in 3650 (98.5%) participants, with mean±SD age of 63.9±0.64 years at inclusion. Only 462 (12.7%) participants were free of plaque, and and 970 (26.6%) had a carotid plaque score of >3. Carotid plaque score predicted ischemic stroke (hazard ratio [HR], 1.25 [95% CI, 1.15–1.36]) and major adverse cardiovascular events (HR, 1.21 [95% CI, 1.14–1.27]) after adjustment for SCORE2 and provided strong incremental prognostic information to SCORE2. The best cutoff value of carotid plaque score for ischemic stroke was >3, with positive predictive value of 2.5% and negative predictive value of 99.3%. Conclusions The carotid plaque score is a strong predictor of ischemic stroke and major adverse cardiovascular events, and it provides incremental prognostic information to SCORE2 for risk prediction. A cutoff score of >3 seems to be suitable to discriminate high‐risk subjects.

• Sourour, Nur; Riveland, Egil Aarstad; Næsgaard, Patrycja; Kjekshus, Harald; Larsen, Alf Inge & Omland, Torbjørn [Show all 8 contributors for this article] (2023). N-terminal pro-B-type natriuretic peptide for prediction of ventricular arrhythmias: Data from the SMASH study. Clinical Cardiology. ISSN 0160-9289. 46(8), p. 989–996. doi: 10.1002/clc.24074. Full text in Research Archive Show summary

  Background Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict heart failure (HF) and mortality, but whether NT-proBNP predicts ventricular arrhythmias (VA) is not clear. Hypothesis We hypothesize that high NT-proBNP concentrations associate with the risk of incident VA, defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia. Methods In a prospective, observational study of patients treated with implantable cardioverter defibrillator (ICD), we analyzed NT-proBNP concentrations at baseline and after mean 1.4 years in association to incident VA. Results We included 490 patients (age 66 ± 12 years, 83% men) out of whom 51% had a primary prevention ICD indication. The median NT-proBNP concentration was 567 (25–75 percentile 203–1480) ng/L and patients with higher concentrations were older with more HF and ICD for primary prevention. During mean 3.1 ± 0.7 years, 137 patients (28%) had ≥1 VA. Baseline NT-proBNP concentrations were associated with the risk of incident VA (hazard ratio [HR]: 1.39, 95% confidence interval [95% CI]: 1.22–1.58, p < .001), HF hospitalizations (HR: 3.11, 95% CI: 2.53–3.82, p < .001), and all-cause mortality (HR: 2.49, 95% CI: 2.04–3.03, p < .001), which persisted after adjusting for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction. The association with VA was stronger in secondary versus primary prevention ICD indication: HR: 1.59 (95% CI: 1.34–1.88 C-statistics 0.71) versus HR: 1.24, 95% CI: 1.02–1.51, C-statistics 0.55), p-for-interaction = 0.06. Changes in NT-proBNP during the first 1.4 years did not associate with subsequent VA. Conclusions NT-proBNP concentrations are associated with the risk of incident VA after adjustment for established risk factors, with the strongest association in patients with a secondary prevention ICD indication.

• Lyngbakken, Magnus Nakrem; Kimenai, Dorien M.; Hveem, Kristian; Dalen, Håvard; Røsjø, Helge Rørvik & Omland, Torbjørn (2023). Patterns of Cardiac Troponin I Concentrations as Risk Predictors of Cardiovascular Disease and Death: The Trøndelag Health Study. American Journal of Medicine. ISSN 0002-9343. 136(9), p. 902–909.e4. doi: 10.1016/j.amjmed.2023.05.009. Full text in Research Archive Show summary

  Background Concentrations of cardiac troponin predict risk of cardiovascular disease and death in the general population. There is limited evidence on changing patterns of cardiac troponin in the years preceding cardiovascular events. Methods We analyzed cardiac troponin I (cTnI) with a high-sensitivity assay in 3272 participants in the Trøndelag Health (HUNT) Study at study visit 4 (2017-2019). Of these, 3198 had measurement of cTnI at study visit 2 (1995-1997), 2661 at study visit 3, and 2587 at all 3 study visits. We assessed the trajectories of cTnI concentrations in the years prior to cardiovascular events using a generalized linear mixed model, with adjustment for age, sex, cardiovascular risk factors, and comorbidities. Results At HUNT4 baseline, median age was 64.8 (range 39.4-101.3) years, and 55% were women. Study participants who were admitted because of heart failure or died from cardiovascular cause on follow-up had a steeper increase in cTnI compared with study participants with no events (P < .001). The average yearly change in cTnI was 0.235 (95% confidence interval, 0.192-0.289) ng/L for study participants with heart failure or cardiovascular death, and −0.022 (95% confidence interval, −0.022 to −0.023) ng/L for study participants with no events. Study participants who experienced myocardial infarction, ischemic stroke, or noncardiovascular mortality exhibited similar cTnI patterns. Conclusions Fatal and nonfatal cardiovascular events are preceded by slowly increasing concentrations of cardiac troponin, independently of established cardiovascular risk factors. Our results support the use of cTnI measurements to identify at-risk subjects who progress to subclinical and later overt cardiovascular disease.

• Sourour, Nur; Riveland, Egil Aarstad; Omland, Torbjørn; Kjekshus, Harald; Larsen, Alf Inge & Røsjø, Helge Rørvik [Show all 7 contributors for this article] (2023). Re: Detailed association between B-type natriuretic peptide levels and ventricular tachyarrhythmia. Clinical Cardiology. ISSN 0160-9289. 46(12), p. 1604–1605. doi: 10.1002/clc.24145. Full text in Research Archive
• Lång, Maarit; Jakob, Stephan M.; Takala, Riikka; Lyngbakken, Magnus Nakrem; Turpeinen, Anu & Omland, Torbjørn [Show all 14 contributors for this article] (2022). The prevalence of cardiac complications and their impact on outcomes in patients with non-traumatic subarachnoid hemorrhage. Scientific Reports. 12(1). doi: 10.1038/s41598-022-24675-8. Full text in Research Archive Show summary

  Abstract Subarachnoid hemorrhage (SAH) is a serious condition, and a myocardial injury or dysfunction could contribute to the outcome. We assessed the prevalence and prognostic impact of cardiac involvement in a cohort with SAH. This is a prospective observational multicenter study. We included 192 patients treated for non-traumatic subarachnoid hemorrhage. We performed ECG recordings, echocardiographic examinations, and blood sampling within 24 h of admission and on days 3 and 7 and at 90 days. The primary endpoint was the evidence of cardiac involvement at 90 days, and the secondary endpoint was to examine the prevalence of a myocardial injury or dysfunction. The median age was 54.5 (interquartile range [IQR] 48.0–64.0) years, 44.3% were male and the median World Federation of Neurological Surgeons (WFNS) score was 2 (IQR 1–4). At day 90, 22/125 patients (17.6%) had left ventricular ejection fractions ≤ 50%, and 2/121 patients (1.7%) had evidence of a diastolic dysfunction as defined by mitral peak E-wave velocity by peak eʹ velocity (E/eʹ) &gt; 14. There was no prognostic impact from echocardiographic evidence of cardiac complications on neurological outcomes. The overall prevalence of cardiac dysfunction was modest. We found no demographic or SAH-related factors associated with 90 days cardiac dysfunction.

• Aagaard, Erika Nerdrum; Lyngbakken, Magnus Nakrem; Kvisvik, Brede Alexander Havneraas; Berge, Trygve; Pervez, Mohammad Osman & Ariansen, Inger Kristine Holtermann [Show all 10 contributors for this article] (2022). Associations between cardiovascular risk factors, biomarkers, and left ventricular mechanical dispersion: insights from the ACE 1950 Study. European Heart Journal Open (EHJ Open). 2(2), p. 1–10. doi: 10.1093/ehjopen/oeac006. Full text in Research Archive Show summary

  Aims Mechanical dispersion measures left ventricular contraction heterogeneity and is associated with the risk of sudden cardiac death. However, the associations between mechanical dispersion and cardiovascular risk factors in early mid-life, and established biomarkers of sub-clinical myocardial injury and dysfunction are not known. We aimed to examine this in the general population. Methods and results During 2012–15, we included 2527 Norwegian individuals from the general population born in 1950, with measurements of mechanical dispersion by 2D speckle tracking echocardiography and concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) available. Mechanical dispersion was calculated as the standard deviation of the contraction duration of 17 strain segments. We assessed the associations between mechanical dispersion, concentrations of hs-cTnT and NT-proBNP, and cardiovascular risk factors collected at a national health screening survey two decades earlier. At echocardiography baseline, median age was 64 (interquartile range 63.5–64.5) years, 49.8% were women, 59.1% had hypertension, and 5.9% reported established coronary artery disease. Median mechanical dispersion was 38.0 (29.5–47.0) ms, median hs-cTnT concentration 6 (4–8) ng/L, and the median NT-proBNP concentration 54 (34–93) ng/L. Mechanical dispersion was associated with both hs-cTnT and NT-proBNP concentrations in multivariable models adjusted for clinical and echocardiographic variables. High body mass index, serum triglyceride concentrations, and low resting heart rate at Age 40 were independently associated with increased mechanical dispersion two decades later. Conclusion Established risk factors at Age 40 are associated with mechanical dispersion two decades later, and mechanical dispersion is cross-sectionally associated with biomarkers of subclinical myocardial injury and dysfunction.

• Figtree, Gemma A.; Vernon, Stephen T.; Hadziosmanovic, Nermin; Sundstrom, Johan; Alfredsson, Joakim & Nicholls, Stephen J. [Show all 11 contributors for this article] (2022). Mortality and Cardiovascular Outcomes in Patients Presenting With Non–ST Elevation Myocardial Infarction Despite No Standard Modifiable Risk Factors: Results From the SWEDEHEART Registry. Journal of the American Heart Association (JAHA). 11(15). doi: 10.1161/JAHA.121.024818. Full text in Research Archive Show summary

  Background A significant proportion of patients with ST‐segment–elevation myocardial infarction (MI) have no standard modifiable cardiovascular risk factors (SMuRFs) and have unexpected worse 30‐day outcomes compared with those with SMuRFs. The aim of this article is to examine outcomes of patients with non–ST‐segment–elevation MI in the absence of SMuRFs. Methods and Results Presenting features, management, and outcomes of patients with non–ST‐segment–elevation MI without SmuRFs (hypertension, diabetes, hypercholesterolemia, smoking) were compared with those with SmuRFs in the Swedish MI registry SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies; 2005–2018). Cox proportional hazard models were used. Out of 99 718 patients with non–ST‐segment–elevation MI, 11 131 (11.2%) had no SMuRFs. Patients without SMuRFs had higher all‐cause and cardiovascular mortality at 30 days (hazard ratio [HR], 1.20 [95% CI, 1.10–1.30], P<0.0001; and HR, 1.25 [95% CI, 1.13–1.38]), a difference that remained after adjustment for age and sex. SMuRF‐less patients were less likely to receive secondary prevention statins (76% versus 82%); angiotensin‐converting enzyme inhibitors/angiotensin receptor blockade (54% versus 72%); or β‐blockers (81% versus 87%, P for all <0.0001), with lowest rates observed in women without SMuRFs. In patients who survived to 30 days, rates of all‐cause and cardiovascular death were lower in patients without SMuRFs compared with those with risk factors, over 12 years. Conclusions One in 10 patients presenting with non–ST‐segment–elevation MI present without traditional risk factors. The excess 30‐day mortality rate in this group emphasizes the need for both improved population‐based strategies for prevention of MI, as well as the need for equitable evidence‐based treatment at the time of an MI.

• Caspersen, Nina Faksvåg; Søyseth, Vidar; Lyngbakken, Magnus Nakrem; Berge, Trygve; Ariansen, Inger Kristine Holtermann & Tveit, Arnljot [Show all 8 contributors for this article] (2022). Treatable Traits in Misdiagnosed Chronic Obstructive Pulmonary Disease: Data from the Akershus Cardiac Examination 1950 Study. COPD: Journal of Chronic Obstructive Pulmonary Disease. ISSN 1541-2555. 9(2), p. 165–180. doi: 10.15326/jcopdf.2021.0265. Full text in Research Archive
• Walle-Hansen, Marte; Berge, Trygve; Vigen, Thea; Myrstad, Marius; Hagberg, Guri & Ihle-Hansen, Hege Beathe [Show all 14 contributors for this article] (2022). Systolic blood pressure at age 40 and cognitive function 25 years later: The Akershus Cardiac Examination (ACE) 1950 Study. Journal of Hypertension. ISSN 0263-6352. 41(1), p. 132–139. doi: 10.1097/HJH.0000000000003312. Full text in Research Archive
• Rønningen, Peter Selmer; Berge, Trygve; Solberg, Magnar Gangås; Enger, Steve; Pervez, Mohammad Osman & Orstad, Eivind Bjørkan [Show all 13 contributors for this article] (2022). Impact of Blood Pressure in the Early 40s on Left Atrial Volumes in the Mid-60s: Data From the ACE 1950 Study. Journal of the American Heart Association (JAHA). 11(11). doi: 10.1161/JAHA.121.023738. Full text in Research Archive Show summary

  Background Echocardiographic measures of left atrial volumes are powerful predictors of cardiovascular events and important for assessing diastolic dysfunction. Despite this, there is limited knowledge of factors influencing left atrial remodeling. In particular, the impact of blood pressure in those in their early 40s on left atrial volumes later in life has not been sufficiently elucidated. Methods and Results We linked data from individuals born in 1950 who participated in the Age 40 Program, and the ACE (Akershus Cardiac Examination) 1950 Study. We divided the study population into quartiles of systolic blood pressure in their early 40s and assessed the proportion of individuals with an enlarged left atrium in their mid‐60s. The associations between blood pressure and left atrial volumes were assessed in linear regression analyses. Of the 2591 individuals included in this study, 1302 (50.3%) were women, and the mean age in the Age 40 Program was 40.1±0.3 years. Systolic blood pressure was 128.1±13.6 mm Hg and diastolic blood pressure was 78.3±9.5 mm Hg. Mean age in the ACE 1950 Study was 64.0±0.6 years. The proportion of individuals with an enlarged left atrium increased across the quartiles of systolic blood pressure (P=0.001). Systolic blood pressure was independently associated with left atrial volumes; the end‐systolic volume was 0.09 mL (95% CI, 0.04–0.14 mL) larger per 1‐mm Hg higher systolic blood pressure. Conclusions Our findings suggest that increased blood pressure in those in their early 40s is relevant for left atrial remodeling later in life.

• Skranes, Julia Brox; Lyngbakken, Magnus Nakrem; Hveem, Kristian; Røsjø, Helge Rørvik & Omland, Torbjørn (2022). Tobacco Consumption and High-Sensitivity Cardiac Troponin I in the General Population: The HUNT Study. Journal of the American Heart Association (JAHA). 11(2), p. 1–9. doi: 10.1161/JAHA.121.021776. Full text in Research Archive Show summary

  Background Cardiac troponins represent a sensitive index of subclinical myocardial injury and are associated with increased risk of cardiovascular events in the general population. Despite positive associations with cardiovascular risk of both cardiac troponins and cigarette smoking, concentrations of cardiac troponin I measured by high‐sensitivity assays (hs‐cTnI) are paradoxically lower in current smokers than in never‐smokers. The impact of smoking intensity and time from smoking cessation on hs‐cTnI remains unknown. Methods and Results hs‐cTnI concentrations were measured in 32028 subjects free from cardiovascular disease enrolled in the prospective, population‐based HUNT (Trøndelag Health Study). Tobacco habits were self‐reported and classified as never (n=14 559), former (n=14 248), and current (n=3221) smokers. Current smokers exhibited significantly lower concentrations of hs‐cTnI than never‐smokers (P<0.001). In adjusted models, both current smoking (−17.3%; 95% CI, −20.6 to −13.9%) and former smoking (−6.6%; 95% CI, −8.7 to −4.5%) were associated with significantly lower hs‐cTnI concentrations. Among former smokers, higher smoking burden (>10 pack‐years) were associated with lower concentrations of hs‐cTnI. Time since smoking cessation was associated with increasing concentrations of hs‐cTnI in a dose‐dependent manner (P for trend<0.001), and subjects who quit smoking >30 years ago had concentrations of hs‐cTnI comparable with those of never‐smokers. Conclusions In the general population, both current and former cigarette smoking is associated with lower concentrations of hs‐cTnI. In former smokers, there was a dose‐response relationship between pack‐years of smoking, and hs‐cTnI. Time since smoking cessation was associated with increasing concentrations of hs‐cTnI, indicating a continuum of hs‐cTnI from current smoker to never‐smokers.

• Sourour, Nur; Riveland, Egil Aarstad; Rømo, Terje; Næsgaard, Patrycja; Kjekshus, Harald & Larsen, Alf Inge [Show all 9 contributors for this article] (2022). QRS fragmentation is associated with increased risk of ventricular arrhythmias in high-risk patients; Data from the SMASH 1 Study. Annals of Noninvasive Electrocardiology. ISSN 1082-720X. 27(5). doi: 10.1111/anec.12985. Full text in Research Archive Show summary

  Introduction QRS fragmentation (fQRS), defined as the presence of additional spikes within the QRS complex, has been associated with myocardial conduction abnormalities and arrhythmogenicity. Objective We aimed to assess whether fQRS is associated with incident ventricular arrhythmias (VA) in high-risk patients treated with implantable cardioverter-defibrillator (ICD) for primary and secondary prevention. Methods In a prospective observational multicenter study, we included 495 patients treated with ICD. fQRS was analyzed according to previously validated criteria, by two physicians blinded for outcome data. Incident VA were obtained from ICD recordings. Results ECG recordings interpretable for fQRS were available in 459 patients (93%), aged 66 ± 12 years with left ventricular ejection fraction 40% ± 13%. fQRS was present in 52 patients (11%) with comparable baseline characteristics to patients without fQRS, except higher age, higher prevalence of coronary artery disease (CAD), lower prevalence of cardiomyopathy, and more frequently a secondary prevention ICD indication. Among patients with native QRS, those with fQRS had similar QRS duration and axis to those without fQRS. During 3.1 ± 0.7 years follow-up, 126 patients (28%) had ≥1 VA . fQRS was associated with increased risk of VA (HR 3.41 [95% CI 2.27–5.13], p < .001), which persisted after adjusting for age, gender, sex, BMI, CAD, heart failure, renal function, ICD indication, QRS duration, QRS axis, Q waves, and bundle branch block. fQRS was more strongly associated with VA in patients with a primary (HR 6.05 [95% CI 3.16–11.60]) versus secondary (HR 2.39 [95% CI 1.41–4.04]) ICD indication (p-for-interaction = .047). Conclusions fQRS is associated with threefold increased risk of VA in high-risk patients, independent of established risk factors.

• Myhre, Peder Langeland; Røsjø, Helge Rørvik; Sarvari, Sebastian; Ukkonen, Heikki; Rademakers, Frank & Engvall, Jan E. [Show all 14 contributors for this article] (2022). Cardiac troponin T and NT-proBNP for detecting myocardial ischemia in suspected chronic coronary syndrome. International Journal of Cardiology. ISSN 0167-5273. 361, p. 14–17. doi: 10.1016/j.ijcard.2022.05.027. Full text in Research Archive Show summary

  Background Elevated N-terminal pro-B-type natriuretic peptides (NT-proBNP) and cardiac troponin T (cTnT) are associated with poor outcome in patients with chronic coronary syndrome (CCS). The performance of these biomarkers in diagnosing ischemia, and their association with myocardial hypoperfusion and hypokinesis is unclear. Methods Patients with suspected CCS (history of angina, estimated cardiovascular risk >15% or a positive stress test) were included in the prospective, multi-center DOPPLER-CIP study. Patients underwent Single Positron Emission Computed Tomography for assessment of ischemia and NT-proBNP and cTnT were measured in venous blood samples. Results We included 430 patients (25% female) aged 64 ± 8 years. Reversible hypoperfusion and hypokinesis were present in 139 (32%) and 89 (21%), respectively. Concentrations of NT-proBNP and cTnT correlated moderately (rho = 0.50, p < 0.001). NT-proBNP and cTnT concentrations (median [IQR]) were higher in patients with versus without reversible ischemia: 150 (73–294) versus 87 (44–192) ng/L and 10 (6–13) versus 7 (4–11) ng/L, respectively (p < 0.001 for both), and the associations persisted after adjusting for possible confounders. The C-statistics to discriminate ischemia ranged from 63%–73%, were comparable for cTnT and NT-proBNP, and higher for hypokinesis than hypoperfusion, and both were superior to exercise electrocardiography and stress echocardiography. Very low concentrations (≤5 ng/L cTnT and ≤ 60 ng/L NT-proBNP) ruled out reversible hypokinesis with negative predictive value >90%. Conclusion cTnT and NT-proBNP are associated with irreversible and reversible ischemia in patients with suspected CCS, particularly hypokinesis. The diagnostic performance was comparable between the biomarkers, and very low concentrations may reliably rule out ischemia.

• Myhre, Peder Langeland; Claggett, Brian; Yu, Bing; Skali, Hicham; Solomon, Scott D. & Røsjø, Helge Rørvik [Show all 13 contributors for this article] (2022). Sex and Race Differences in N-Terminal Pro-B-type Natriuretic Peptide Concentration and Absolute Risk of Heart Failure in the Community. JAMA cardiology. ISSN 2380-6583. 7(6), p. 623–631. doi: 10.1001/jamacardio.2022.0680. Full text in Research Archive
• Lyngbakken, Magnus Nakrem; Kvisvik, Brede Alexander Havneraas; Berge, Trygve; Pervez, Mohammad Osman; Aagaard, Erika Nerdrum & Ariansen, Inger Kristine Holtermann [Show all 10 contributors for this article] (2022). Serial blood pressure measurements, left ventricular remodelling and cardiovascular outcomes. European Journal of Clinical Investigation. ISSN 0014-2972. 53(1). doi: 10.1111/eci.13876. Full text in Research Archive Show summary

  Background Hypertension is a risk factor for the development of cardiovascular disease. Whether serial blood pressure (BP) measurements are more closely associated with subclinical left ventricular (LV) remodelling and better predict risk of cardiovascular events over individual BP measurements are not known. Methods We assessed systolic BP, diastolic BP and pulse pressure at several time points during adulthood in 1333 women and 1211 men participating in the Akershus Cardiac Examination 1950 Study. We defined serial BP measurements as the sum of averaged BPs from adjacent consecutive visits indexed to total exposure time between measurements. We assessed the associations between serial and individual BP measurements and (1) LV structure, function and volumes and (2) incident myocardial infarction, ischemic stroke, heart failure and cardiovascular death. Results All indices of higher serial BP measurements were associated with increased indexed LV mass, and the associations were stronger than those of individual BP measurements. Serial diastolic BP pressure was strongly and inversely associated with LV systolic function, while higher serial systolic BP was primarily associated with higher LV volumes. Both serial systolic (incidence rate ratio [IRR] 1.10, 95% CI 1.03 to 1.17) and diastolic BPs (IRR 1.14, 95% CI 1.02 to 1.27) were associated with increased incidence of clinical events. Conclusion In healthy community dwellers without established cardiovascular disease, different serial BP indices associate strongly with LV remodelling and cardiovascular outcomes. Whether the use of serial BP indices for guiding treatment is superior to individual measurements should be explored in additional prospective studies.

• Berge, Kristian; Brynildsen, Jon; Røysland, Ragnhild; Strand, Heidi; Christensen, Geir & Høiseth, Arne Didrik [Show all 9 contributors for this article] (2022). Prognostic value of cardiac biomarkers and National Early Warning Score 2 in acute dyspnoea. Open heart. 9(1). doi: 10.1136/openhrt-2021-001938. Full text in Research Archive Show summary

  Objective Patients hospitalised with acute dyspnoea due to acute heart failure (AHF) have a grave prognosis, but the European Society of Cardiology guidelines recommend no system to risk stratify these patients. The prognostic value of combining National Early Warning Score (NEWS) 2 and established cardiac biomarkers is not known. Methods We measured high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and calculated NEWS2 in 314 patients with acute dyspnoea within 24 hours of hospitalisation. Their prognostic merits were assessed in the total cohort and for the subgroup with AHF separately. Results The median age was 73 (quartile (Q) 1–3, 63–81) years, 48% were women and 143 patients (46%) were hospitalised with AHF. The 114 patients (36%) who died during follow-up (median 823 days, Q1–3, 471–998) had higher concentrations of hs-cTnT (62 vs 33 ng/L, p&lt;0.001) and NT-proBNP (6995 vs 2605 ng/L, p&lt;0.001), and higher NEWS2 (6.1 vs 4.5 points, p&lt;0.001), compared with survivors. Patients with increased vs low NEWS2 clinical risk had higher mortality rates in adjusted analyses in the total cohort (HR 2.11, 95% CI 1.28 to 3.48) and in patients with AHF (HR 2.00, 95% CI 1.54 to 2.60). NEWS2 provided incremental prognostic information compared with biomarkers alone for the total cohort: area under the curve 0.72 vs 0.70, p=0.042, and for the subpopulation with AHF: 0.70 vs 0.67, p=0.014. Conclusion NEWS2 predicts long-term mortality in patients hospitalised due to acute dyspnoea and the subgroup with AHF and provide incremental prognostic information to hs-cTnT and NT-proBNP.

• Lyngbakken, Magnus Nakrem; Rønningen, Peter Selmer; Solberg, Magnar Gangås; Berge, Trygve; Brynildsen, Jon & Aagaard, Erika Nerdrum [Show all 11 contributors for this article] (2022). Prediction of incident atrial fibrillation with cardiac biomarkers and left atrial volumes. Heart. ISSN 1355-6037. doi: 10.1136/heartjnl-2022-321608. Full text in Research Archive Show summary

  Objective Atrial fibrillation is a common arrhythmia associated with risk of stroke, heart failure and death. We aimed to elucidate the associations of cardiac biomarkers, echocardiographic left atrial volumetric indices and risk of prevalent and incident atrial fibrillation in the general population. Methods We assessed cardiac troponin T (cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), maximum (LAVi max ) and minimum (LAVi min ) indexed left atrial volumes and left atrial emptying fraction (LAEF) in subjects born in 1950 participating in the prospective observational cohort, Akershus Cardiac Examination 1950 Study. The Cohorts for Heart and Ageing Research in Genomic Epidemiology for Atrial Fibrillation risk score and sex was used to adjust for residual risk of atrial fibrillation. Results Out of 3487 subjects, 157 (4.5%) had prevalent and 123 (3.5%) had incident atrial fibrillation. Echocardiographic left atrial volumes and cardiac biomarkers associated with prevalent atrial fibrillation, but GDF-15 was non-significant in adjusted analysis. Incident atrial fibrillation was predicted by LAVi max (adjusted HR 1.51, 95% CI 1.30 to 1.75), LAVi min (adjusted HR 1.52, 95% CI 1.35 to 1.72), LAEF (adjusted HR 1.24, 95% CI 1.04 to 1.48) and NT-proBNP (adjusted HR 1.57, 95% CI 1.32 to 1.85). cTnT and NT-proBNP provided incremental prognostic information to left atrial volumes, but GDF-15 demonstrated no prognostic value for incident atrial fibrillation. Conclusions In the general population, echocardiographic left atrial volumetric indices and NT-proBNP, but not cTnT and GDF-15, associate with prevalent atrial fibrillation and with risk of incident atrial fibrillation. cTnT and NT-proBNP provide incremental prognostic information to echocardiography.

• Myhre, Peder Langeland; Heck, Siri Lagethon; Skranes, Julia Brox; Prebensen, Christian Haugland; Jonassen, Christine M & Berge, Trygve [Show all 15 contributors for this article] (2021). Cardiac pathology 6 months after hospitalization for COVID-19 and association with the acute disease severity. American Heart Journal. ISSN 0002-8703. 242, p. 61–70. doi: 10.1016/j.ahj.2021.08.001. Full text in Research Archive Show summary

  Background Coronavirus disease 2019 (COVID-19) may cause myocardial injury and myocarditis, and reports of persistent cardiac pathology after COVID-19 have raised concerns of long-term cardiac consequences. We aimed to assess the presence of abnormal cardiovascular resonance imaging (CMR) findings in patients recovered from moderate-to-severe COVID-19, and its association with markers of disease severity in the acute phase. Methods Fifty-eight (49%) survivors from the prospective COVID MECH study, underwent CMR median 175 [IQR 105-217] days after COVID-19 hospitalization. Abnormal CMR was defined as left ventricular ejection fraction (LVEF) <50% or myocardial scar by late gadolinium enhancement. CMR indices were compared to healthy controls (n = 32), and to circulating biomarkers measured during the index hospitalization. Results Abnormal CMR was present in 12 (21%) patients, of whom 3 were classified with major pathology (scar and LVEF <50% or LVEF <40%). There was no difference in the need of mechanical ventilation, length of hospital stay, and vital signs between patients with vs without abnormal CMR after 6 months. Severe acute respiratory syndrome coronavirus 2 viremia and concentrations of inflammatory biomarkers during the index hospitalization were not associated with persistent CMR pathology. Cardiac troponin T and N-terminal pro-B-type natriuretic peptide concentrations on admission, were higher in patients with CMR pathology, but these associations were not significant after adjusting for demographics and established cardiovascular disease. Conclusions CMR pathology 6 months after moderate-to-severe COVID-19 was present in 21% of patients and did not correlate with severity of the disease. Cardiovascular biomarkers during COVID-19 were higher in patients with CMR pathology, but with no significant association after adjusting for confounders. Trial Registration COVID MECH Study ClinicalTrials.gov Identifier: NCT04314232

• Sigurdardóttir, Fjóla Dögg; Lyngbakken, Magnus; Hveem, Kristian; Hrubos-Strøm, Harald; Røsjø, Helge & Redline, Susan [Show all 7 contributors for this article] (2021). Insomnia symptoms and subclinical myocardial injury: Data from the Nord-Trøndelag Health (HUNT) study. Journal of Sleep Research. ISSN 0962-1105. 30(5). doi: 10.1111/jsr.13299. Full text in Research Archive Show summary

  Insomnia symptoms are associated with increased risk of heart failure (HF) and cardiovascular (CV) mortality. We hypothesised that insomnia symptoms are cross-sectionally associated with increased cardiac troponin I (cTnI), a biomarker of subclinical myocardial injury, and that phenotyping by insomnia symptoms and cTnI enhances longitudinal risk stratification in the general population. In a population-based study, cTnI was measured in 8,398 participants (median age 49 years, 55% women), who had answered questionnaires regarding insomnia symptoms. Association between cTnI and insomnia symptoms was assessed by linear regression analysis for each response category of a sleep questionnaire. Insomnia symptoms were defined as having difficulty falling asleep almost every night, difficulty maintaining sleep almost every night, and/or non-restorative sleep once a week or more. The primary outcome measure was a composite endpoint of CV mortality or first admission for HF. In all, 844 participants reported insomnia symptoms, 585 (69%) were women. Those with insomnia symptoms had marginally, but significantly higher median cTnI than those without insomnia symptoms, (median [interquartile range] 3.4 [2.4–5.2] ng/L versus 3.2 [2.2–4.9] ng/L; p = .014), but there was no association between any insomnia symptom and cTnI in unadjusted linear regression models (β 0.06, 95% confidence interval [CI] −0.01 to 0.12). In adjusted analyses, participants with insomnia symptoms and increased cTnI were at increased risk of the composite endpoint (hazard ratio 1.71, 95% CI 1.04–2.79) compared to participants with insomnia symptoms and low cTnI. In the general population, insomnia symptoms are not associated with biochemical evidence of subclinical myocardial injury.

• Moksnes, Marta Riise; Røsjø, Helge; Richmond, Anne; Lyngbakken, Magnus N; Graham, Sarah E & Hansen, Ailin Falkmo [Show all 30 contributors for this article] (2021). Genome-wide association study of cardiac troponin i in the general population. Human Molecular Genetics. ISSN 0964-6906. 30(21), p. 2027–2039. doi: 10.1093/hmg/ddab124. Full text in Research Archive Show summary

  Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

• Aakre, Kristin Moberg; Ottesen, Anett Hellebø; Strand, Heidi; Faaren, Arne L.; Alaour, Bashir & Torsvik, Janniche [Show all 11 contributors for this article] (2021). Biological variation of secretoneurin; a novel cardiovascular biomarker implicated in arrhythmogenesis. Clinical Biochemistry. ISSN 0009-9120. 98, p. 74–77. doi: 10.1016/j.clinbiochem.2021.09.014. Full text in Research Archive Show summary

  Background Secretoneurin is a novel prognostic biomarker that may predict mortality in heart failure and the occurrence of ventricular arrhythmias. This study reports the within subject variation (CVI), between subject variation (CVG), reference change values (RCV) and index of individuality (II) of secretoneurin. Methods Thirty healthy volunteers were included. Non-fasting samples were obtained between 8 and 10 am once a week for ten weeks. Secretoneurin was analyzed in duplicate using ELISA. No outliers were present according to Burnett and Reeds‘ criteria. Simple linear regression did not identify significant trends. Variance homogeneity in the analytical variance and CVI were tested using Cochrane’s and Bartlett’s tests and four participants were excluded. Calculation of CVI, CVG and RCV were done on ln transformed data as described by Fokkema, the II was calculated using retransformed data. Results The median age of the participants was 36 years and 53% were female. Non-fasting glucose, eGFR(CKD-EPI), cTnT and NT-proBNP concentrations were within the normal range. Median secretoneurin concentrations were 38 pmol/L (women) and 33 pmol/L (men), p-value < 0.001. CVI and CVG were 9.8% (CI 8.7% to 11.0%) and 20.0 (CI 15.4% to 28.0%), respectively. RCV were 38.7% (CI 35.5% to 42.7%) and −27.9 (CI −29.9 to −26.2) and the II were 0.60 (CI 0.42–0.78). No gender differences were present. Conclusion Secretoneurin has a fairly low CVI, CVG, RCV and II, indicating that it could be suitable as a diagnostic or prognostic biomarker and that delta values in serial samplings may be preferable for identifying clinical changes.

• Heck, Siri Lagethon; Mecinaj, Albulena; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette & Fagerland, Morten [Show all 12 contributors for this article] (2021). Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): Extended follow-up of a 2×2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Circulation. ISSN 0009-7322. 143(25), p. 2431–2440. doi: 10.1161/CIRCULATIONAHA.121.054698. Full text in Research Archive Show summary

  Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti–human epidermal growth factor receptor–2 antibodies and radiotherapy is associated with cancer treatment–related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01434134.

• Berge, Kristian; Lyngbakken, Magnus Nakrem; Omland, Torbjørn; Juliebø, Vibeke; Schirmer, Henrik & Røsjø, Helge Rørvik (2021). Ytterligere læringsmomenter fra et kardiologisk perspektiv. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(1). doi: 10.4045/tidsskr.20.1025. Full text in Research Archive
• Myhre, Peder Langeland; Lyngbakken, Magnus Nakrem; Berge, Trygve; Røysland, Ragnhild; Aagaard, Erika Nerdrum & Pervez, Mohammad Osman [Show all 13 contributors for this article] (2021). Diagnostic Thresholds for Pre-Diabetes Mellitus and Diabetes Mellitus and Subclinical Cardiac Disease in the General Population: Data From the ACE 1950 Study. Journal of the American Heart Association (JAHA). 10(11). doi: 10.1161/JAHA.120.020447. Full text in Research Archive Show summary

  Background Diabetes mellitus (DM) is associated with left ventricular remodeling and incident heart failure, but the association between glycated hemoglobin A1c (HbA1c) and subclinical cardiac disease is not established. We aimed to determine the associations between HbA1c and (1) echocardiographic measures of left ventricular structure and function, and (2) cardiovascular biomarkers: cardiac troponin T, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), and CRP (C‐reactive protein). Methods and Results Participants (n=3688) born in 1950 from the population‐based ACE (Akershus Cardiac Examination) 1950 Study were classified as DM (HbA1c≥6.5% or self‐reported DM), pre‐DM (HbA1c 5.7%–6.5%), and no‐DM (HbA1c<5.7%). DM, pre‐DM, and no‐DM were classified in 380 (10%), 1630 (44%), and 1678 (46%) participants, respectively. Mean age was 63.9±0.7 years, mean body mass index was 27.2±4.4 kg/m2, and 49% were women. Higher HbA1c was associated with worse left ventricular systolic (ejection fraction and global longitudinal strain) and diastolic (E/e'‐ratio) function, myocardial injury (cardiac troponin T), inflammation (CRP), and impaired neurohormonal homeostasis (NT‐proBNP) (P<0.001 in unadjusted and P<0.01 in adjusted analysis for all). The associations between HbA1c and cardiovascular biomarkers were independent of the echocardiographic variables, and vice versa. Associations were nonlinear (P<0.05 for nonlinearity) and appeared stronger in the pre‐DM range of HbA1c than the no‐DM and DM range. Conclusions HbA1c was associated with indexes of subclinical cardiovascular disease, and this was more pronounced in pre‐DM. Our results suggest that cardiovascular preventive measures should be considered also in subjects with hyperglycemia and HbA1c below the established DM cutoff. Registration clinicaltrials.gov. Identifier: NCT01555411.

• Lyngbakken, Magnus Nakrem; Hveem, Kristian; Røsjø, Helge Rørvik & Omland, Torbjørn (2021). Subclinical myocardial injury and risk of COVID-19 in the general population: The Trøndelag Health Study. Clinical Chemistry. ISSN 0009-9147. 68(3), p. 473–475. doi: 10.1093/clinchem/hvab267. Full text in Research Archive
• Axfors, Cathrine; Schmitt, Andreas; Janiaud, Perrine; Hooft, Janneke; Abd-Elsalam, Sherief & Abdo, Ehab [Show all 50 contributors for this article] (2021). Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nature Communications. 12. doi: 10.1038/s41467-021-22446-z. Full text in Research Archive Show summary

  Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

• Lyngbakken, Magnus Nakrem; Lemos, James A. De; Hveem, Kristian; Røsjø, Helge Rørvik & Omland, Torbjørn (2021). Lifetime obesity trends are associated with subclinical myocardial injury: The Trøndelag health study. Journal of Internal Medicine. ISSN 0954-6820. p. 1–10. doi: 10.1111/joim.13391. Full text in Research Archive Show summary

  Background Obesity is associated with subclinical myocardial injury as quantified by concentrations of cardiac troponin T, but whether lifetime excess weight history is associated with increased concentrations of cardiac troponin I (cTnI) and how indices of abdominal adiposity and glycemic dysregulation affect these associations remain unclear. Methods We analyzed cTnI with a high-sensitivity assay in 9739 participants in the Trøndelag Health (HUNT) Study at study visit 4 (2017–2019). BMI was assessed at study Visit 1 (1984–1986), 2 (1995–1997), 3 (2006–2008), and 4. Results Median age at visit 4 was 68.7 years and 59% were women. Concentrations of cTnI were detectable in 84.1% of study participants, with a median of 2.5 (1.5–4.5 ng/L). We identified three clusters of BMI trajectories from visit 1 to 4, (1) stable normal weight, (2) stable overweight, and (3) stable obesity. Participants in clusters 2 and 3 were at increased risk of elevated concentrations of cTnI at visit 4 (odds ratio 1.27, 95% CI 1.09–1.47, and odds ratio 1.70, 95% CI 1.33–2.17, p for trend <0.001). Participants in cluster 3 had 22.0 (95% CI 14.1–29.9) higher concentrations of cTnI compared to participants in cluster 1 (p for trend <0.001). Dysregulated glucose metabolism and abdominal obesity did not influence our results. Conclusions Individuals with stable overweight or obesity are at increased risk of subclinical myocardial injury, independently of glycemic dysregulation and abdominal adiposity. Our data support a direct detrimental effect of long-standing obesity on cardiovascular health.

• Rutkovskiy, Arkady; Lyngbakken, Magnus; Dahl, Mai Britt; Bye, Anja; Pedersen, Marit Holmefjord & Wisløff, Ulrik [Show all 10 contributors for this article] (2021). Circulating MicroRNA-210 Concentrations in Patients with Acute Heart Failure: Data from the Akershus Cardiac Examination 2 Study. Clinical Chemistry. ISSN 0009-9147. 67(6), p. 889–898. doi: 10.1093/clinchem/hvab030. Full text in Research Archive Show summary

  Background MicroRNA (miR)-210 expression is induced by acute and chronic hypoxia and provides prognostic information in patients with aortic stenosis and acute coronary syndrome. We hypothesized that circulating miR-210 concentrations could provide diagnostic and prognostic information in patients with acute heart failure (HF). Methods We measured miR-210 concentrations in serum samples on admission from 314 patients hospitalized for acute dyspnea and 9 healthy control subjects. The diagnostic and prognostic properties of miR-210 were tested in patients after adjudication of all diagnoses and with median follow-up of 464 days. Results All patients and control subjects had miR-210 concentrations within the range of detection, and the analytical variation was low as the coefficient of variation of synthetic spike-in RNA was 4%. Circulating miR-210 concentrations were increased in patients with HF compared to healthy control subjects, but miR-210 concentrations did not separate patients with acute HF (n = 143) from patients with non-HF-related dyspnea (n = 171): the area under the curve was 0.50 (95% CI 0.43–0.57). Circulating miR-210 concentrations were associated with mortality (n = 114) after adjustment for clinical risk factors (hazard ratio 1.65 [95% CI 1.03–2.62] per unit miR-210 increase), but this association was attenuated and not significant after adjustment for established cardiac protein biomarkers. Conclusions Circulating miR-210 concentrations are associated with mortality, but do not add to established protein biomarkers for diagnosis or prognosis in patients with acute dyspnea.

• Lundin, Knut Erik Aslaksen; Røsjø, Helge Rørvik; Myhren, Hilde; Kvale, Dag & Rosvold, Elin Olaug (2021). Legeutdanning i en pandemitid. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141. doi: 10.4045/tidsskr.21.0581. Full text in Research Archive
• Lyngbakken, Magnus; Vigen, Thea; Ihle-Hansen, Håkon; Brynildsen, Jon; Berge, Trygve & Rønning, Ole M. [Show all 9 contributors for this article] (2021). Cardiac troponin I measured with a very high sensitivity assay predicts subclinical carotid atherosclerosis: The Akershus Cardiac Examination 1950 Study. Clinical Biochemistry. ISSN 0009-9120. 93, p. 59–65. doi: 10.1016/j.clinbiochem.2021.04.005. Full text in Research Archive Show summary

  Aims Concentrations of cardiac troponin I (cTnI) are associated with incident ischemic stroke and predict the presence and severity of coronary atherosclerosis. Accordingly, we hypothesized that concentrations of cTnI measured with a very high sensitivity (hs-) assay would be associated with subclinical stages of carotid atherosclerosis in the general population. Methods We measured hs-cTnI on the Singulex Clarity System in 1745 women and 1666 men participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants were free from known coronary heart disease and underwent extensive cardiovascular phenotyping at baseline, including carotid ultrasound. We quantified carotid atherosclerosis by the carotid plaque score, carotid intima-media thickness (cIMT) and the presence of hypoechoic plaques. Results Concentrations of hs-cTnI were measurable in 99.8% of study participants and were significantly associated with increased carotid plaque score (odds ratio for quartile 4 of hs-cTnI 1.59, 95% CI 1.22 to 2.07, p for trend < 0.001) and cIMT (odds ratio for quartile 4 of hs-cTnI 1.57, 95% CI 1.02 to 2.42, p for trend = 0.036), but not with the presence of hypoechoic plaques. hs-cTnI concentrations significantly improved reclassification and discrimination models in predicting carotid plaques when added to cardiovascular risk factors, no improvements were evident in predicting cIMT or hypoechoic plaques. Conclusion Concentrations of cTnI measured with a very high sensitivity assay are predictive of carotid atherosclerotic burden, a phenomenon likely attributable to common risk factors of subclinical myocardial injury, coronary and carotid atherosclerosis.

• Myhre, Peder Langeland; Ottesen, Anett Hellebø; Faaren, Arne L.; Tveit, Sjur Hansen; Springett, Jon & Pyylampi, Johanna [Show all 11 contributors for this article] (2021). Performance of a Novel Research-Use-Only Secretoneurin ELISA in Patients with Suspected Acute Coronary Syndrome: Comparison with an Established Secretoneurin Radioimmunoassay. Cardiology. ISSN 0008-6312. 146(5), p. 566–574. doi: 10.1159/000517444. Full text in Research Archive Show summary

  Background: Circulating secretoneurin (SN) concentrations, as measured by established radioimmunoassay (RIA), risk stratify patients with cardiovascular disease. We now report data for a recently developed research-use-only SN enzyme-linked immunosorbent assay (ELISA) in patients with suspected acute coronary syndrome (ACS). Methods: SN ELISA was developed according to industry standards and tested in 401 unselected chest pain patients. Blood samples were drawn <24 h from admission, and we adjudicated all hospitalizations as ACS or non-ACS. The mean follow-up was 6.2 years. Results: SN ELISA with 2 monoclonal sheep anti-SN antibodies has a measuring range of 10–250 pmol/L and demonstrates excellent analytical precision and accuracy across the range of SN concentrations. SN measured by ELISA and RIA correlated in the chest pain patients: rho = 0.39, p < 0.001. SN concentrations were higher in ACS patients (n = 161 [40%]) than in non-ACS patients (n = 240) for both assays, with an area under the curve (AUC) of 0.66 (95% CI: 0.61–0.71) for ELISA and 0.59 (0.54–0.65) for RIA. SN concentrations were also higher in nonsurvivors (n = 65 [16%]) than survivors, with an AUC of 0.72 (0.65–0.79) for ELISA versus 0.64 (0.56–0.72) for RIA, p = 0.007, for difference between assays. Adjusting for age, sex, blood pressure, previous myocardial infarction, atrial fibrillation, and heart failure in multivariable analysis, SN concentrations as measured by ELISA, but not RIA, remained associated with mortality, with a hazard ratio of 1.71 (1.03–2.84), p = 0.038. Conclusions: The novel SN ELISA has excellent performance, higher AUC for diagnosis, and superior prognostic accuracy compared to the established RIA in chest pain patients.

• Aarsetøy, Reidun; Omland, Torbjørn; Røsjø, Helge; Strand, Heidi; Lindner, Thomas Werner & Aarsetøy, Hildegunn [Show all 8 contributors for this article] (2020). N-terminal pro-B-type natriuretic peptide as a prognostic indicator for 30-day mortality following out-of-hospital cardiac arrest: A prospective observational study. BMC Cardiovascular Disorders. 20:382, p. 1–10. doi: 10.1186/s12872-020-01630-x. Full text in Research Archive Show summary

  Background Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA). Methods We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors (p <  0.001) and significantly associated with 30-days all-cause mortality in univariate analysis, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% confidence interval (CI), 2.1–10.1), p <  0.001. This association was no longer significant in multivariable analysis applying continuous values, [HR 0.96, (95% CI, 0.64–1.43), p = 0.84]. Similar results were obtained by dividing the population by survival at hospital admission, excluding non-return of spontaneous circulation (ROSC) patients on scene [HR 0.93 (95% CI, 0.50–1.73), P = 0.83]. We also noted that NT-proBNP was significantly higher in asystole- as compared to VF-patients, p <  0.001. Conclusions Early-on levels of hs-cTnT, copeptin and NT-proBNP did not provide independent prognostic information following OHCA. Prediction was unaffected by excluding on-scene non-ROSC patients in the multivariable analysis.

• Chandra, Anupam; Røsjø, Helge; Svensson, My Hanna Sofia; Vigen, Thea; Ihle-Hansen, Håkon & Orstad, Eivind Bjørkan [Show all 14 contributors for this article] (2020). Plasma linoleic acid levels and cardiovascular risk factors: results from the Norwegian ACE 1950 Study. European Journal of Clinical Nutrition. ISSN 0954-3007. doi: 10.1038/s41430-020-0641-4. Full text in Research Archive Show summary

  Background A high intake of linoleic acid (LA), the major dietary polyunsaturated fatty acid (PUFA), has previously been associated with reduced cardiovascular (CV) morbidity and mortality in observational studies. However, recent secondary analyses from clinical trials of LA-rich diet suggest harmful effects of LA on CV health. Methods A total of 3706 participants, all born in 1950, were included in this cross-sectional study. We investigated associations between plasma phospholipid levels of LA and CV risk factors in a Norwegian general population, characterized by a relative low LA and high marine n-3 PUFA intake. The main statistical approach was multivariable linear regression. Results Plasma phospholipid LA levels ranged from 11.4 to 32.0 wt%, with a median level of 20.8 wt% (interquartile range 16.8–24.8 wt%). High plasma LA levels were associated with lower serum low-density lipoprotein cholesterol levels (standardized regression coefficient [Std. β-coeff.] −0.04, p = 0.02), serum triglycerides (Std. β-coeff. −0.10, p < 0.001), fasting plasma glucose (Std. β-coeff. −0.10, p < 0.001), body mass index (Std. β-coeff. −0.13, p < 0.001), systolic and diastolic blood pressure (Std. β-coeff. −0.04, p = 0.03 and Std. β-coeff. −0.02, p = 0.02, respectively) and estimated glomerular filtration rate (Std. β-coeff. −0.09, p < 0.001). We found no association between plasma LA levels and high-density lipoprotein cholesterol levels, glycated hemoglobin, carotid intima-media thickness, or C-reactive protein. Conclusion High plasma LA levels were favorably associated with several CV risk factors in this study of a Norwegian general population.

• Chandra, Anupam; Lyngbakken, Magnus; Eide, Ivar Anders; Røsjø, Helge; Vigen, Thea & Ihle-Hansen, Håkon [Show all 13 contributors for this article] (2020). Plasma trans fatty acid levels, cardiovascular risk factors and lifestyle: Results from the Akershus cardiac examination 1950 study. Nutrients. 12(5). doi: 10.3390/nu12051419. Full text in Research Archive Show summary

  Intake of industrially produced trans fatty acids (iTFAs) has previously been associated with dyslipidemia, insulin resistance, hypertension and inflammation, as well as increased cardiovascular (CV) morbidity and mortality. iTFA intake declined in Norway after the introduction of legislative bans against iTFA consumption. However, the relationship between the current iTFA intake and CV health is unclear. The aim of the present study was to investigate the association between current iTFA intake, reflected by plasma iTFA levels, and established CV risk factors. We also examined the associations between plasma ruminant TFA levels and CV risk factors. In this cross-sectional study, we included 3706 participants from a Norwegian general population, born in 1950 and residing in Akershus County, Norway. The statistical method was multivariable linear regression. Plasma iTFA levels were inversely associated with serum triglycerides (p &lt; 0.001), fasting plasma glucose (p &lt; 0.001), body mass index (p &lt; 0.001), systolic and diastolic blood pressure (p = 0.001 and p = 0.03) and C-reactive protein (p = 0.001). Furthermore, high plasma iTFA levels were associated with higher education and less smoking and alcohol consumption. We found that plasma ruminant trans fatty acids (rTFA) levels were favorably associated with CV risk factors. Furthermore, plasma iTFA levels were inversely associated with CV risk factors. However, our results might have been driven by lifestyle factors. Overall, our findings suggest that the current low intake of iTFAs in Norway does not constitute a threat to CV health.

• Røsjø, Helge; Hijazi, Ziad; Omland, Torbjørn; Westerbergh, Johan; Lyngbakken, Magnus & Alexander, J.H. [Show all 12 contributors for this article] (2020). Cardiac troponin is associated with cardiac outcomes in men and women with atrial fibrillation, insights from the ARISTOTLE trial. Journal of Internal Medicine. ISSN 0954-6820. 288(2), p. 248–259. doi: 10.1111/joim.13072. Full text in Research Archive Show summary

  Background Cardiac troponin T (cTnT) and I (cTnI) concentrations provide strong prognostic information in anticoagulated patients with atrial fibrillation (AF). Whether the associations between cardiac troponin concentrations and mortality and morbidity differ by sex is not known. Objectives To assess whether men and women have different concentrations and prognostic value of cTnT and cTnI measurements in anticoagulated patients with AF. Methods cTnT and cTnI concentrations were measured with high‐sensitivity (hs) assays in EDTA plasma samples obtained from the multicentre ARISTOTLE trial, which randomized patients with AF and at least one risk factor for stroke or systemic embolic event to warfarin or apixaban. Patients were stratified according to sex and the associations between hs‐troponin concentrations, and all‐cause death, cardiac death, myocardial infarction, stroke or systemic embolic event and major bleeding were assessed in multivariable regression models. Results We found higher cardiac troponin concentrations in men (n = 9649) compared to women (n = 5331), both for hs‐cTnT (median 11.8 [Q1‐3 8.1–18.0] vs. 9.6 [6.7–14.3] ng L−1, P < 0.001) and hs‐cTnI (5.8 [3.4–10.8] vs. 4.9 [3.1–8.8] ng L−1, P < 0.001). Adjusting for baseline demographics, comorbidities and medications, men still had significantly higher hs‐troponin concentrations than women. C‐reactive protein and N‐terminal pro‐B‐type natriuretic peptide concentrations were higher in female patients. Both hs‐cTnT and hs‐cTnI concentrations were associated with all clinical outcomes similarly in men and women (p‐value for interaction >0.05 for all end‐points). Conclusion Men have higher hs‐troponin concentrations than women in AF. Regardless of sex, hs‐troponin concentrations remain similarly associated with adverse clinical outcomes in anticoagulated patients with AF.

• Lyngbakken, Magnus; Berdal, Jan Erik; Eskesen, Arne N; Kvale, Dag; Olsen, Inge Christoffer & Rueegg, Corina Silvia [Show all 11 contributors for this article] (2020). A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nature Communications. 11:5284, p. 1–6. doi: 10.1038/s41467-020-19056-6. Full text in Research Archive Show summary

  Abstract Here, we randomized 53 patients hospitalized with coronavirus disease 2019 (COVID-19) to hydroxychloroquine therapy (at a dose of 400 mg twice daily for seven days) in addition to standard care or standard care alone (ClinicalTrials.gov Identifier, NCT04316377). All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission. Treatment with hydroxychloroquine did not result in a significantly greater rate of decline in SARS-CoV-2 oropharyngeal viral load compared to standard care alone during the first five days. Our results suggest no important antiviral effect of hydroxychloroquine in humans infected with SARS-CoV-2.

• Rønningen, Peter Selmer; Berge, Trygve; Solberg, Magnar Gangås; Enger, Steve; Nygård, Ståle & Pervez, Mohammad Osman [Show all 12 contributors for this article] (2020). Sex differences and higher upper normal limits for left atrial end-systolic volume in individuals in their mid-60s: data from the ACE 1950 Study. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 21(5), p. 501–507. doi: 10.1093/ehjci/jeaa004. Full text in Research Archive
• Berge, Kristian; Lyngbakken, Magnus; Myhre, Peder Langeland; Brynildsen, Jon; Røysland, Ragnhild & Strand, Heidi [Show all 10 contributors for this article] (2020). High-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide in acute heart failure: Data from the ACE 2 study. Clinical Biochemistry. ISSN 0009-9120. p. 1–7. doi: 10.1016/j.clinbiochem.2020.11.009. Full text in Research Archive Show summary

  Background To assess if cardiac troponins can improve diagnostics of acute heart failure (AHF) and provide prognostic information in patients with acute dyspnea. Methods We measured cardiac troponin T with a high-sensitivity assay (hs-cTnT) in 314 patients hospitalized with acute dyspnea. The index diagnosis was adjudicated and AHF patients were stratified into AHF with reduced or preserved ejection fraction (HFrEF/HFpEF). The prognostic and diagnostic merit of hs-cTnT was compared to the merit of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results In the total population, median age was 73 (quartile [Q] 1–3 63–81) years and 48% were women. One-hundred-forty-three patients were categorized as AHF (46%) and these patients had higher hs-cTnT concentrations than patients with non-AHF-related dyspnea: median 38 (Q1-3 22–75) vs. 13 (4–25) ng/L; p < 0.001. hs-cTnT concentrations were similar between patients with HFrEF and HFpEF (p = 0.80), in contrast to NT-proBNP, which was higher in HFrEF (p < 0.001). C-statistics for discriminating HFpEF from non-AHF-related dyspnea was 0.80 (95% CI 0.73–0.86) for hs-cTnT, 0.79 (0.73–0.86) for NT–proBNP, and 0.83 (0.76–0.89) for hs-cTnT and NT-proBNP in combination. Elevated hs-cTnT remained associated with HFpEF in logistic regression analysis after adjusting for demographics, comorbidities and renal function. During median 27 months of follow-up, 114 (36%) patients died in the total population. Higher hs-cTnT concentrations were associated with increased risk of all-cause mortality after adjustment for clinical variables and NT-proBNP: hazard ratio 1.30 (95% CI 1.07–1.58), p = 0.009. Conclusion hs-cTnT measurements improve diagnostic accuracy for HFpEF and provide independent prognostic information in unselected patients with acute dyspnea.

• Lyngbakken, Magnus; Kvisvik, Brede Alexander; Aagaard, Erika Nerdrum; Berge, Trygve; Pervez, Mohammad Osman & Brynildsen, Jon [Show all 10 contributors for this article] (2020). B-Type Natriuretic Peptide Is Associated with Indices of Left Ventricular Dysfunction in Healtahy Subjects from the General Population: The Akershus Cardiac Examination 1950 Study. Clinical Chemistry. ISSN 0009-9147. doi: 10.1093/clinchem/hvaa257. Full text in Research Archive Show summary

  Abstract Background Concentrations of B-type natriuretic peptide (BNP) reflect myocardial distension and stress, and are associated with poor prognosis in patients with cardiovascular disease. Accordingly, we hypothesized that concentrations of BNP would be associated with indices of adverse left ventricular (LV) remodeling and early stages of LV systolic and diastolic dysfunction in healthy participants from the general population. Methods We measured BNP in 1757 women and 1677 men free from known coronary heart disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive cardiovascular phenotyping at baseline, including detailed echocardiography with assessment of indexed LV mass (LVMI), diastolic [tissue Doppler e’, E/e’ ratio, indexed left atrial volume (LAVI), maximal tricuspid regurgitation velocity (TRVmax), and E/A ratio], and systolic [global longitudinal strain (GLS) and LV ejection fraction (LVEF)] function. Results Study participants with the highest BNP concentrations had higher GLS, LVMI, e’, E/e’ ratio, LAVI, TRVmax, and E/A ratio. In adjusted analyses, both GLS and LVEF exhibited significant nonlinear associations with BNP, with reduced LV systolic function observed in both the low and high concentration range of BNP. Conclusions In healthy participants recruited from the general population, concentrations of BNP exhibit nonlinear associations with LV systolic function, and both low and high concentrations are associated with reduced LV systolic function. This supports the notion that natriuretic peptides are beneficial and elicit cardioprotective effects, and may have important implications for the interpretation of BNP measurements in the general population.

• Omland, Torbjørn; Prebensen, Christian; Røysland, Ragnhild; Søvik, Signe; Sørensen, Vibecke & Røsjø, Helge [Show all 9 contributors for this article] (2020). Established Cardiovascular Biomarkers Provide Limited Prognostic Information in Unselected Patients Hospitalized with COVID-19. Circulation. ISSN 0009-7322. 19, p. 1878–1880. doi: 10.1161/CIRCULATIONAHA.120.050089. Full text in Research Archive
• Myhre, Peder Langeland; Prebensen, Christian; Strand, Heidi; Røysland, Ragnhild; Jonassen, Christine M. & Rangberg, Anbjørg [Show all 12 contributors for this article] (2020). Growth Differentiation Factor-15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized with COVID-19. Circulation. ISSN 0009-7322. doi: 10.1161/CIRCULATIONAHA.120.050360. Full text in Research Archive
• Gilmour, Brian Christopher; Gudmundsrud, Ruben; Frank, Johannes; Hov, Amund; Lautrup, Sofie Hindkjær & Aman, Yahyah [Show all 18 contributors for this article] (2020). Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Mechanisms of Ageing and Development. ISSN 0047-6374. 186, p. 1–6. doi: 10.1016/j.mad.2020.111208. Full text in Research Archive Show summary

  Nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in life and health through the regulation of energy biogenesis, redox homeostasis, cell metabolism, and the arbitration of cell survival via linkages to apoptosis and autophagic pathways. The importance of NAD+ in ageing and healthy longevity has been revealed from laboratory animal studies and early-stage clinical testing. While basic researchers and clinicians have investigated the molecular mechanisms and translation potential of NAD+, there are still major gaps in applying laboratory science to design the most effective trials. This mini-review was based on the programme and discussions of the 3rd NO-Age Symposium held at the Akershus University Hospital, Norway on the 28th October 2019. This symposium brought together leading basic researchers on NAD+ and clinicians who are leading or are going to perform NAD+ augmentation-related clinical studies. This meeting covered talks about NAD+ synthetic pathways, subcellular homeostasis of NAD+, the benefits of NAD+ augmentation from maternal milk to offspring, current clinical trials of the NAD+ precursor nicotinamide riboside (NR) on Ataxia-Telangiectasia (A-T), Parkinson’s disease (PD), post-sepsis fatigue, as well as other potential NR-based clinical trials. Importantly, a consensus is emerging with respect to the design of clinical trials in order to measure meaningful parameters and ensure safety.

• Lyngbakken, Magnus; Aagaard, Erika Nerdrum; Kvisvik, Brede Alexander; Berge, Trygve; Pervez, Mohammad Osman & Brynildsen, Jon [Show all 10 contributors for this article] (2020). Cardiac troponin I and T are associated with left ventricular function and structure: Data from the Akershus Cardiac Examination 1950 Study. Clinical Chemistry. ISSN 0009-9147. 66(4), p. 567–578. doi: 10.1093/clinchem/hvaa023. Full text in Research Archive Show summary

  Abstract Background Concentrations of cardiac troponin I (cTnI) and T (cTnT) are associated with clinical cardiac outcomes, but do not correlate closely in subjects recruited from the general population. Accordingly, we hypothesized that cTnI and cTnT concentrations would be influenced by different cardiovascular (CV) and non-CV risk factors and reflect different CV phenotypes. Methods We measured cTnI and cTnT with last generation assays in 1236 women and 1157 men with no known CV disease participating in the prospective observational Akershus Cardiac Examination 1950 Study. All study participants underwent extensive CV phenotyping at baseline, including detailed echocardiography. Results Concentrations of cTnI were measurable in 60.3% and cTnT in 72.5% of study participants (P &amp;lt; 0.001), and correlated moderately (r = 0.53; P &amp;lt; 0.001). cTnI was more strongly associated with male sex (P = 0.018), higher education (P &amp;lt; 0.001), history of hypertension (P &amp;lt; 0.001), and age (P &amp;lt; 0.001), whereas cTnT was more strongly associated with eGFR (P = 0.015). Both cTnI and cTnT were inversely associated with global longitudinal strain and positively associated with LV mass index (LVMI) in analyses adjusted for CV risk factors. The association between cTnI and LVMI was stronger than the association between cTnT and LVMI (P = 0.035). Concentrations of cTnI improved diagnostic accuracy for LV hypertrophy when added to established CV risk factors, but concentrations of cTnT did not improve these models further. Conclusions In a large community-based cohort examined with extensive echocardiography, concentrations of cTnI and cTnT are associated with subclinical LV hypertrophy and dysfunction. Concentrations of cTnI appear superior to cTnT in predicting subclinical LV hypertrophy.

• Velle-Forbord, Torbjørn; Eidlaug, Maria; Debik, Julia Barbara; Sæther, Julie Caroline; Follestad, Turid & Nauman, Javaid [Show all 11 contributors for this article] (2019). Circulating microRNAs as predictive biomarkers of myocardial infarction: Evidence from the HUNT study. Atherosclerosis. ISSN 0021-9150. 289, p. 1–7. doi: 10.1016/j.atherosclerosis.2019.07.024. Full text in Research Archive Show summary

  Background and aims Several risk prediction models for coronary heart disease (CHD) are available today, however, they only explain a modest proportion of the incidence. Circulating microRNAs (miRs) have recently been associated with processes in CHD development, and may therefore represent new potential risk markers. The aim of the study was to assess the incremental value of adding circulating miRs to the Framingham Risk Score (FRS). Methods This is a case-control study with a 10-year observation period, with fatal and non-fatal myocardial infarction (MI) as endpoint. At baseline, ten candidate miRs were quantified by real-time polymerase chain reaction in serum samples from 195 healthy participants (60–79 years old). During the follow-up, 96 participants experienced either a fatal (n = 36) or a non-fatal MI (n = 60), whereas the controls (n = 99) remained healthy. By using best subset logistic regression, we identified the miRs that together with the FRS for hard CHD best predicted future MI. The model evaluation was performed by 10-fold cross-validation reporting area under curve (AUC) from the receiver operating characteristic curve (ROC). Results The best miR-based logistic regression risk-prediction model for MI consisted of a combination of miR-21-5p, miR-26a-5p, mir-29c-3p, miR-144-3p and miR-151a-5p. By adding these 5 miRs to the FRS, AUC increased from 0.66 to 0.80. In comparison, adding other important CHD risk factors (waist-hip ratio, triglycerides, glucose, creatinine) to the FRS only increased AUC from 0.66 to 0.68. Conclusions Circulating levels of miRs can add value on top of traditional risk markers in predicting future MI in healthy individuals.

• Myhre, Peder Langeland; Lyngbakken, Magnus; Tveit, Sjur Hansen; Røsjø, Helge & Omland, Torbjørn (2019). Cardiac imaging and circulating biomarkers for primary prevention in the era of precision medicine. Expert Review of Precision Medicine and Drug Development. 4(5), p. 299–308. doi: 10.1080/23808993.2019.1660162. Full text in Research Archive Show summary

  Introduction: Current primary prevention guidelines do not strongly support the use of cardiovascular imaging and circulating biomarkers in risk assessment. Still, an increasing body of evidence suggests that important prognostic information can be obtained from imaging and biomarker measurements. Areas covered: In this review, we describe the most important imaging modalities (coronary computed tomography, myocardial perfusion imaging, carotid intima media thickness, echocardiography and cardiac magnetic resonance imaging) and circulating biomarkers (cardiac troponins, B-type natriuretic peptides and C-reactive protein) for risk prediction in people without known cardiovascular disease. We discuss both the prognostic performance and clinical utility of these biomarkers in the era of primary prevention with increased focus on precision medicine. Finally, we comment on the use of cardiac biomarkers in screening for additional work-up with cardiac imaging and the combination of the entities in risk prediction. Expert opinion: We believe future primary prevention should, to a larger extent, integrate measurements of cardiovascular biomarkers and non-invasive imaging to enhance the precision of subclinical disease detection and risk stratification. The use of cardiovascular biomarkers as a screening tool for further testing with non-invasive imaging may be a cost-effective strategy.

• Chandra, Anupam; Røsjø, Helge; Eide, Ivar Anders; Vigen, Thea; Ihle-Hansen, Håkon & Orstad, Eivind Bjørkan [Show all 13 contributors for this article] (2019). Plasma marine n-3 polyunsaturated fatty acids and cardiovascular risk factors: data from the ACE 1950 study. European Journal of Nutrition. ISSN 1436-6207. p. 1–11. doi: 10.1007/s00394-019-02007-3. Full text in Research Archive Show summary

  Abstract Purpose A high intake of marine n-3 polyunsaturated fatty acids (PUFAs) might improve cardiovascular (CV) health. We conducted a cross-sectional study to investigate associations between plasma phospholipid levels of marine n-3 PUFAs and CV risk factors, educational level, physical activity and smoking habits. Methods A total of 3706 individuals from a general population, all born in 1950 and residing in Akershus County, Norway, were included in this study. The main statistical approach was multivariable adjusted linear regression. Results Plasma marine n-3 PUFA levels ranged from 2.7 to 20.3 wt%, with a median level of 7.7 wt% (interquartile range 4.3–11.1 wt%). High levels of plasma marine n-3 PUFAs were associated with lower serum triglycerides [Standardized regression coefficient (Std.β-coeff.) − 0.14, p < 0.001], body mass index (Std. β-coeff. −0.08, p < 0.001), serum creatinine (Std. β-coeff. -0.03, p = 0.05), C-reactive protein levels (Std. β-coeff. – 0.03, p = 0.04), higher levels of serum high-density lipoprotein cholesterol (Std. β-coeff. 0.08, p < 0.001) and low-density lipoprotein cholesterol (Std. β-coeff. 0.04, p = 0.003). High levels of plasma marine n-3 PUFAs were also associated with lower glycated hemoglobin (Std. β-coeff. – 0.04, p = 0.01), however, only in individuals without diabetes. We found no associations between plasma marine n-3 PUFA levels and fasting plasma glucose or carotid intima-media thickness. High levels of plasma marine n-3 PUFAs were associated with higher educational level, more physical activity and lower prevalence of smoking. Conclusion In this cross-sectional study of Norwegian individuals born in 1950, high levels of plasma marine n-3 PUFAs were favourably associated with several CV risk factors, suggesting that fish consumption might improve CV health.

• Brynildsen, Jon; Petaja, Liisa; Myhre, Peder Langeland; Lyngbakken, Magnus; Nygård, Ståle & Stridsberg, Mats [Show all 11 contributors for this article] (2019). Circulating Secretoneurin Concentrations After Cardiac Surgery: Data From the FINNish Acute Kidney Injury Heart Study. Critical Care Medicine. ISSN 0090-3493. 47(5), p. e412–e419. doi: 10.1097/CCM.0000000000003670. Full text in Research Archive
• Myhre, Peder Langeland; Claggett, Brian; Ballantyne, Christie M; Selvin, Elizabeth; Røsjø, Helge & Omland, Torbjørn [Show all 9 contributors for this article] (2019). Association between Circulating Troponin Concentrations, Left Ventricular Systolic and Diastolic Functions, and Incident Heart Failure in Older Adults. JAMA cardiology. ISSN 2380-6583. 4(10), p. 997–1006. doi: 10.1001/jamacardio.2019.3113. Full text in Research Archive
• Vigen, Thea; Ihle-Hansen, Håkon; Lyngbakken, Magnus; Berge, Trygve; Thommessen, Bente & Ihle-Hansen, Hege [Show all 11 contributors for this article] (2019). Carotid Atherosclerosis is Associated with Middle Cerebral Artery Pulsatility Index. Journal of Neuroimaging (JON). ISSN 1051-2284. doi: 10.1111/jon.12684. Full text in Research Archive Show summary

  BACKGROUND AND PURPOSE Pulsatility index (PI) in the middle cerebral artery (MCA) is considered a measure of peripheral vascular resistance. Several established cardiovascular risk factors are common for both MCA PI and carotid atherosclerosis. Accordingly, in the present study we hypothesized an association between ultrasound‐derived indices of carotid atherosclerosis and MCA PI. METHODS All residents in Akershus County, born in 1950, were invited to a cardiovascular examination, The Akershus Cardiac Examination (ACE) 1950 Study (2012‐2015). A thorough ultrasound examination was performed to assess indices of atherosclerosis in the carotid arteries, and PI in the MCAs. In all, 3154 (85.1%) had adequate transcranial and carotid data. Associations between indices of carotid atherosclerosis and MCA PI were assessed by regression analyses adjusted for established cardiovascular risk factors. RESULTS Mean age was 64 (standard deviation [SD]: .6) years, and 1,357 (43%) were women. Mean MCA PI was .97 (SD: .17). Participants in the upper quartile of MCA PI had higher pulse pressure, more frequently hypertension, diabetes mellitus, and a history of coronary artery disease. Both carotid plaque score (B .007 [95% CI: .003‐.010]) and carotid intimamedia thickness (B .173 [95% CI: .120‐.226]) were significantly associated with MCA PI in adjusted analysis. The model R 2 was .055. CONCLUSION In a population‐based sample of middle‐aged adults, ultrasound‐derived indices of carotid atherosclerosis were independently associated with MCA PI. However, the overall explained variance of MCA PI was low, suggesting other factors than atherosclerosis and cardiovascular risk factors to play an important role for MCA PI.

• Kvisvik, Brede Alexander; Aagaard, Erika Nerdrum; Mørkrid, Lars; Røsjø, Helge; Lyngbakken, Magnus & Smedsrud, Marit Kristine [Show all 11 contributors for this article] (2019). Mechanical dispersion as a marker of left ventricular dysfunction and prognosis in stable coronary artery disease. The International Journal of Cardiovascular Imaging. ISSN 1569-5794. 35, p. 1265–1275. doi: 10.1007/s10554-019-01583-z. Full text in Research Archive Show summary

  Assessment of global longitudinal strain (GLS) is superior to ejection fraction (EF) in the evaluation of left ventricular (LV) function in patients with stable coronary artery disease (CAD). However, the role of mechanical dispersion (MD) in this context remains unresolved. We aimed to evaluate the potential role of MD as a marker of LV dysfunction and long-term prognosis in stable CAD. EF, GLS and MD were assessed in 160 patients with stable CAD, 1 year after successful coronary revascularization. Serum levels of high-sensitivity cardiac troponin I (hs-cTnI) and amino-terminal pro B-type natriuretic peptide (NT-proBNP) were quantified as surrogate markers of LV dysfunction. The primary endpoint was defined as all-cause mortality, the secondary endpoint was defined as the composite of all-cause mortality and hospitalization for acute myocardial infarction or heart failure during follow-up. Whereas no associations between EF and the biochemical markers of LV function were found, both GLS and MD correlated positively with increasing levels of hs-cTnI (R = 0.315, P < 0.001 and R = 0.442, P < 0.001, respectively) and NT-proBNP (R = 0.195, P = 0.016 and R = 0.390, P < 0.001, respectively). Median MD was 46 ms (interquartile range [IQR] 37–53) and was successfully quantified in 96% of the patients. During a median follow-up of 8.4 (IQR 8.2–8.8) years, 14 deaths and 29 secondary events occurred. MD was significantly increased in non-survivors, and provided incremental prognostic value when added to EF and GLS. NT-proBNP was superior to the echocardiographic markers in predicting adverse outcomes. MD may be a promising marker of LV dysfunction and adverse prognosis in stable CAD.

• Vigen, Thea; Ihle-Hansen, Håkon; Lyngbakken, Magnus; Berge, Trygve; Thommessen, Bente & Ihle-Hansen, Hege [Show all 12 contributors for this article] (2019). Blood pressure at age 40 predicts carotid atherosclerosis two decades later: Data from the Akershus Cardiac Examination 1950 Study. Journal of Hypertension. ISSN 0263-6352. 37(10), p. 1982–1990. doi: 10.1097/HJH.0000000000002131. Full text in Research Archive Show summary

  Objective: We assessed the impact of a single time-point measurement of SBP, DBP and pulse pressure at the age of 40, on carotid plaque burden, echolucent plaques and carotid intima–media thickness late midlife. Methods: Individuals participating in two separate studies, 23 years apart, defined our cohort (n = 2714). ‘The Age 40 Program’, a nationwide Norwegian cardiovascular screening survey, performed 1985–1999, assessed cardiovascular risk factors and lifestyle variables at age 40. ‘The ACE 1950 Study’, a population-based cohort study on individuals born in 1950, performed 2012–2015, included ultrasound examinations of the carotid arteries. Blood pressure (BP) determinants of carotid atherosclerosis were assessed by regression models adjusted for cardiovascular risk factors at age 40, and late midlife BP. Results: The participants, 50.3% women, had a mean age of 40 (SD 0.3) years in the first study, and 64 (SD 0.6) years in the second. At age 40, mean SBP was 128 (SD 14) mmHg, mean DBP was 78 (SD 10) mmHg and mean pulse pressure was 50 (SD 9) mmHg. SBP and DBP at age 40 predicted carotid plaque burden in late midlife. Only DBP predicted echolucent plaques, and none of the BP components predicted carotid intima–media thickness. Conclusion: A single time-point measurement of SBP and DBP at age 40 is associated with carotid plaque burden late midlife, also after adjustment for other cardiovascular risk factors at age 40, and of late midlife BP. Our findings emphasize the strong association between BP and atherosclerosis.

• Brynildsen, Jon; Myhre, Peder Langeland; Lyngbakken, Magnus; Klæboe, Lars Gunnar; Stridsberg, Mats & Christensen, Geir Arve [Show all 9 contributors for this article] (2019). Circulating secretoneurin concentrations in patients with moderate to severe aortic stenosis. Clinical Biochemistry. ISSN 0009-9120. 71, p. 17–23. doi: 10.1016/j.clinbiochem.2019.06.008. Full text in Research Archive Show summary

  Background Secretoneurin (SN) concentrations provide important prognostic information in patients with myocardial dysfunction. Whether preoperative SN concentrations improve risk assessment in patients with moderate to severe aortic stenosis (AS) is unknown. Methods We included 57 patients with moderate to severe AS referred for presurgical evaluation. All patients were examined with comprehensive echocardiography, electrocardiogram (ECG), and biochemical measurements and compared to 10 age- and sex-matched healthy subjects. Results Median (quartile 1–3) SN concentrations were 141 (121–163) pmol/L in AS patients and 132 (106–148) pmol/L in control subjects (p = .17). Lower estimated creatinine clearance and use of diuretics, but not standard ECG or echocardiographic indices and cardiac biomarkers, were associated with increasing SN concentrations. Fifteen patients (26%) died during 3.5 years median follow-up. SN concentrations were higher in non-survivors than survivors: 156 (133–209) vs. 140 (116–155) pmol/L, p = .007. Higher SN concentrations were associated with increased risk of mortality also after adjustment for established risk indices, biomarkers, and status regarding valvular surgery: hazard ratio per lnSN 15.13 (95% CI 1.05–219.00); p = .046. Receiver operating characteristics area under the curve for SN to predict mortality was 0.74 (95% CI 0.60–0.88) compared to 0.73 (0.59–0.87) for high-sensitivity cardiac troponin T and 0.67 (0.51–0.82) for N-terminal pro-B-type natriuretic peptide. The previously identified cut-off of SN >204 pmol/L in cardiac surgical patients predicted mortality also in this cohort. Conclusions SN concentrations improve risk assessment in patients with moderate to severe AS by providing additional prognostic information to established risk indices such as echocardiography, ECG, and established cardiac biomarkers.

• Ihle-Hansen, Håkon; Vigen, Thea; Berge, Trygve; Hagberg, Guri; Engedal, Knut & Rønning, Ole M. [Show all 12 contributors for this article] (2019). Carotid Atherosclerosis and Cognitive Function in a General Population Aged 63-65 Years: Data from the Akershus Cardiac Examination (ACE) 1950 Study. Journal of Alzheimer's Disease. ISSN 1387-2877. 70(4), p. 1041–1049. doi: 10.3233/JAD-190327. Full text in Research Archive Show summary

  Background:Studies on the relationship between carotid atherosclerosis and cognitive function in subjects from the general population are few and results have been inconsistent. Objective:We aimed to investigate the association between carotid atherosclerotic burden and cognitive function in a cross-sectional analysis of a population-based cohort aged 63–65 years. Methods:All habitants born in 1950 from Akershus County, Norway were invited to participate. A linear regression model was used to assess the association between carotid atherosclerosis and cognitive function. We used carotid plaque score as a measure of carotid atherosclerotic burden and the Montreal Cognitive Assessment (MoCA) for global cognitive function. Results:We analyzed 3,413 individuals aged 63–65 with mean MoCA score 25.3±2.9 and 87% visible carotid plaques. We found a negative correlation between carotid plaque score and MoCA score (r = –0.14, p < 0.001), but this association was lost in multivariable analysis. In contrast, diameter or area of the thickest plaque was independently associated with MoCA score. Lower educational level, male sex, current smoking, and diabetes were also associated with lower MoCA score in multivariable analysis. Conclusion:Carotid atherosclerotic burden was, unlike other measures of advanced carotid atherosclerosis, not independently associated with global cognitive function.

• Lyngbakken, Magnus; Røsjø, Helge; Holmen, Oddgeir Lingaas; Dalen, Håvard; Hveem, Kristian & Omland, Torbjørn (2019). Temporal changes in cardiac troponin i are associated with risk of cardiovascular events in the general population: The Nord-Trøndelag health study. Clinical Chemistry. ISSN 0009-9147. 65(7), p. 871–881. doi: 10.1373/clinchem.2018.301069. Full text in Research Archive Show summary

  BACKGROUND:Cardiac troponins are associated with car-diovascular risk in the general population, but whethertemporal changes in cardiac troponin I provide indepen-dent prognostic information remains uncertain. Using alarge community-based cohort with follow-up close tothe present day, we aimed to investigate the associationsbetween temporal changes in cardiac troponin and car-diovascular events.METHODS:We measured cardiac troponin I with a high-sensitivity assay (hs-cTnI) in 4805 participants attendingboth the second (HUNT 2, 1995–97) and third wave(HUNT 3, 2006–2008) of the prospective observationalNord-Trøndelag Health (HUNT) Study. Wecon-structed statistical models with both relative and absolutechanges of hs-cTnI from HUNT 2 to HUNT 3. Acomposite end point of cardiovascular death or firstadmission for myocardial infarction or heart failurewas generated.RESULTS:Participants with relative decrease in hs-cTnIwere more frequently younger and female and had lowerblood pressure and body mass index. Participants withrelative increase in hs-cTnI more frequently were olderand male, with higher systolic blood pressure. The ad-justed hazard ratio (HR) for relative increase in hs-cTnIwas 1.68 (95% CI, 1.16–2.42) and the adjusted HR forrelative decrease was 1.19 (95% CI, 0.84–1.68). Abso-lute increases in hs-cTnI exhibited similar prognosticproperties as relative increases in hs-cTnI. The most re-cent measurement of hs-cTnI outperformed the changevariables in discrimination and reclassification models.CONCLUSIONS:Both relative and absolute increases in hs-cTnI are independently associated with cardiovascularrisk. For refinement of risk prediction models, the mostrecent measurement of hs-cTnI should be preferred inclinical practice.

• Lyngbakken, Magnus; Myhre, Peder Langeland; Røsjø, Helge & Omland, Torbjørn (2019). Novel biomarkers of cardiovascular disease: Applications in clinical practice. Critical reviews in clinical laboratory sciences. ISSN 1040-8363. 56(1), p. 33–60. doi: 10.1080/10408363.2018.1525335. Full text in Research Archive Show summary

  Measurement of biomarkers has revolutionized the work-up of patients with suspected cardiovascular disease. The most widely used contemporary cardiovascular biomarkers are the natriuretic peptides in the diagnosis and prognosis of heart failure and cardiac troponins in the diagnosis of acute myocardial infarction. Numerous other biomarkers pertaining to diagnosis, prognosis, and risk prediction have been identified, but few have made their way to clinical practice. In this review, we will initially describe the fundamental approach to evaluate a novel biomarker. Before implementation of a biomarker into clinical practice, several stringent criteria related to its clinical utility are required. Essential statistical metrics such as discrimination, calibration, and reclassification are required to properly evaluate prediction models. We will then discuss the biomarkers according to main groups of cardiovascular pathology:1.  myocardial injury (cardiac troponins, heart-type fatty acid-binding protein, cardiac myosin binding protein-C);2.  myocardial stress (A-type and B-type natriuretic peptides, mid-regional pro-adrenomedullin, copeptin); 3.  inflammation (C-reactive protein, interleukin 6, growth differentiation factor 15, soluble suppressor of tumorigenicity 2, galectin-3);4.  platelet activation (soluble CD40 ligand, P-selectin);5.  plaque instability (lipoprotein-associated phospholipase A2, matrix metalloproteinase-9);6.  systemic stress (catecholamines, granin proteins);7.  calcium homeostasis (secretoneurin). Finally, we will discuss novel applications of cardiovascular biomarkers, more specifically prediction of ventricular arrhythmias, and the use of biomarkers in composite risk prediction models.

• Aagaard, Erika Nerdrum; Kvisvik, Brede Alexander; Pervez, Mohammad Omar; Lyngbakken, Magnus; Berge, Trygve & Enger, Steve [Show all 12 contributors for this article] (2019). Left ventricular mechanical dispersion in a general population: Data from the Akershus Cardiac Examination 1950 study. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 21. doi: 10.1093/ehjci/jez210. Full text in Research Archive
• Chandra, Anupam; Røsjø, Helge; Eide, Ivar Anders; Vigen, Thea; Ihle-Hansen, Håkon & Orstad, Eivind Bjørkan [Show all 13 contributors for this article] (2019). Plasma marine n-3 polyunsaturated fatty acids and cardiovascular risk factors: data from the ACE 1950 study. European Journal of Nutrition. ISSN 1436-6207. doi: 10.1007/s00394-019-02007-3. Full text in Research Archive
• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Eken, Olav Søvik; Sadredini, Mani; Myhre, Peder Langeland & Shen, Xin [Show all 24 contributors for this article] (2019). Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia. Circulation: Arrhythmia and Electrophysiology. ISSN 1941-3149. 12(4). doi: 10.1161/CIRCEP.118.007045. Full text in Research Archive Show summary

  Background: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. Methods: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia–induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9–induced overexpression. Interactions between SN and CaMKIIδ were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca2+ homeostasis examined by fluorescence (fluo-4) and patch-clamp recordings in isolated cardiomyocytes. Results: SN levels were elevated in patients with CPVT and following ventricular arrhythmia–induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9–induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ and RyR inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca2+ current. Conclusions: SN production is upregulated in conditions with cardiomyocyte Ca2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.

• Berge, Trygve; Lyngbakken, Magnus; Ihle-Hansen, Håkon; Brynildsen, Jon; Pervez, Mohammad Osman & Aagaard, Erika Nerdrum [Show all 14 contributors for this article] (2018). Prevalence of atrial fibrillation and cardiovascular risk factors in a 63-65 years old general population cohort: The Akershus Cardiac Examination (ACE) 1950 Study. BMJ Open. 8:e021704(7), p. 1–9. doi: 10.1136/bmjopen-2018-021704. Full text in Research Archive Show summary

  Objectives To investigate the sex-specific prevalence of atrial fibrillation (AF), including subclinical AF found by screening in a general population aged 63–65 years. The prevalence of cardiovascular risk factors and their association with AF will also be investigated. Methods: All participants underwent extensive cardiovascular examinations, including 12-lead ECG. History of AF and other cardiovascular diseases were self-reported. Subsequent validation of all reported or detected AF diagnoses was performed. Results: Mean age was 63.9±0.7 years. Prevalence of ECG-verified AF was 4.5% (women 2.4%, men 6.4%; p<0.001), including screen-detected AF in 0.3% (women 0.1%, men 0.6%; p<0.01). Hypertension was found in 62.0% (women 57.8%, men 66.0%; p<0.001). Overweight or obesity was found in 67.6% (women 59.8%, men 74.9%; p<0.001). By multivariate logistic regression, risk factors associated with AF were height (OR 1.67 per 10 cm; 95% CI 1.26 to 2.22; p<0.001), weight (OR 1.15 per 10 kg; 95% CI 1.01 to 1.30; p=0.03), hypertension (OR 2.49; 95% CI 1.61 to 3.86; p<0.001), heart failure (OR 3.51; 95% CI 1.71 to 7.24; p=0.001), reduced estimated glomerular filtration rate (OR 2.56; 95% CI 1.42 to 4.60; p<0.01) and at least one first-degree relative with AF (OR 2.32; 95% CI 1.63 to 3.31; p<0.001), whereas male sex was not significantly associated (OR 1.00; 95% CI 0.59 to 1.68; p=0.99). Conclusion: In this cohort from the general population aged 63–65 years, we found a higher prevalence of known AF than previously reported below the age of 65 years. The additional yield of single time point screening for AF was low. Body size and comorbidity may explain most of the sex difference in AF prevalence at this age.

• Caspersen, Nina Faksvåg; Røsjø, Helge; Flyvbjerg, Allan; Bjerre, Mette; Randby, Anna & Hrubos-Strøm, Harald [Show all 8 contributors for this article] (2018). The association between circulating adiponectin levels, lung function and adiposity in subjects from the general population; data from the Akershus Sleep Apnea Project. BMC Pulmonary Medicine. 18(54). doi: 10.1186/s12890-018-0618-4. Full text in Research Archive Show summary

  Background Circulating adiponectin (ADPN) levels are inversely associated with disease severity in patients with chronic obstructive pulmonary disease (COPD), while studies assessing the relationship between ADPN and lung function in subjects from the general population have shown diverging results. Accordingly, we hypothesized that ADPN would be associated with lung function in a population-based sample and tested how abdominal adiposity, metabolic syndrome, and systemic inflammation influenced this association. Methods We measured total ADPN in serum, forced vital capacity (FVC) and forced expiratory volume during the 1st second (FEV1) in 529 participants (median 50 years, 54.6% males) recruited from the general population. We assessed the association between ADPN and lung function by multivariate linear regression analyses and adjusted for age, gender, height, smoking habits, weight, body mass index, waist-hip ratio, metabolic syndrome, obstructive sleep apnoea (OSA) and C-reactive protein. Results The median (interquartile range) level of serum ADPN was 7.6 (5.4–10.4) mg/L. ADPN levels were positively associated with FVC % of predicted (beta 3.4 per SD adiponectin, p < 0.001)) in univariate linear regression analysis, but the association was attenuated in multivariate analysis (standardized beta 0.03, p = 0.573)). Among co-variates only WHR significantly attenuated the relationship. ADPN levels were also associated with FEV1% of predicted in bivariate analysis that adjusted for smoking (beta 1.4, p = 0.042)), but this association was attenuated and no longer significant in multivariate analysis (standardized beta -0.06, p = 0.254)). Conclusion In this population-based sample no association between ADPN and lung function was evident after adjustment for covariates related to adiposity.

• Berge, Kristian; Lyngbakken, Magnus; Einvik, Gunnar; Winther, Jacob Andreas; Brynildsen, Jon & Røysland, Ragnhild [Show all 11 contributors for this article] (2018). Diagnostic and prognostic properties of procalcitonin in patients with acute dyspnea: Data from the ACE 2 Study. Clinical Biochemistry. ISSN 0009-9120. 59, p. 62–68. doi: 10.1016/j.clinbiochem.2018.07.006. Full text in Research Archive

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• Axfors, Cathrine; Schmitt, Andreas M.; Janiaud, Perrine; Hooft, Janneke van’t; Abd-Elsalam, Sherief & Abdo, Ehab F. [Show all 94 contributors for this article] (2024). Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials(Nature Communications, (2021), 12, (1), 10.1038/s41467-021-22446-z). Nature Communications. 15(1). doi: 10.1038/s41467-024-45360-6. Full text in Research Archive
• Sæther, Julie Caroline; Follestad, Turid; Klevjer, Marie; Giskeødegård, Guro F.; Bathen, Tone Frost & Gigante, Bruna [Show all 10 contributors for this article] (2023). Circulating lipoprotein subfractions and microRNAs as potential biomarkers for improved risk prediction of myocardial infarction: the HUNT study. Full text in Research Archive
• Myhre, Peder Langeland; Lyngbakken, Magnus Nakrem; Røsjø, Helge Rørvik & Omland, Torbjørn (2020). Removing stable and adding precision to chronic coronary artery disease. International Journal of Cardiology. ISSN 0167-5273. 316, p. 54–56. doi: 10.1016/j.ijcard.2020.04.063. Full text in Research Archive
• Tveit, Sjur Hansen; Myhre, Peder Langeland; Røsjø, Helge Rørvik & Omland, Torbjørn (2020). Reply: The complementary role of cardiac troponin I and cardiac troponin T. Clinical Biochemistry. ISSN 0009-9120. 78, p. 42–42. doi: 10.1016/j.clinbiochem.2020.02.011. Full text in Research Archive
• Lyngbakken, Magnus; Berdal, Jan Erik; Eskesen, Arne N; Kvale, Dag; Christoffer, Olsen Inge & Rangberg, Anbjørg [Show all 10 contributors for this article] (2020). Norwegian Coronavirus Disease 2019 (NO COVID-19) Pragmatic Open label Study to assess early use of hydroxychloroquine sulphate in moderately severe hospitalised patients with coronavirus disease 2019: A structured summary of a study protocol for a randomised controlled trial. Trials. 21. doi: 10.1186/s13063-020-04420-0. Full text in Research Archive
• Aarsetøy, Reidun; Omland, Torbjørn; Røsjø, Helge; Strand, Heidi; Aarsetøy, Hildegunn & Staines, Harry [Show all 7 contributors for this article] (2019). N-terminal Pro-B-Type Natriuretic Peptide may serve as a prognostic indicator for 30-day mortality following out-of-hospital cardiac arrest, whereas both high-sensitivity cardiac troponin-T and copeptin did not yield prognostic information. Circulation 2019; 140: Suppl 2, Abstract 135. Full text in Research Archive Show summary

  Abstract Introduction: Sudden cardiac arrest (SCA) may be due to different underlying conditions. Prior heart disease is a major risk factor, and coronary artery disease is the most common underlying cause. Hs-cTnT and copeptin are used for early diagnosis of acute myocardial infarction, and may also serve as prognostic indicators following an acute coronary syndrome. NT-proBNP is a marker of heart failure and may act as a predictor of mortality in SCA patients. These three biomarkers in relation to ventricular fibrillation (VF) and asystole on scene during resuscitation has not, to our knowledge, been evaluated. Hypothesis: We hypothesized that early-on levels of hs-cTnT, copeptin and NT-proBNP may relate to prognosis. Methods: From February 2007 until November 2010 blood samples were collected from patients aged > 18 years with out-of-hospital cardiac arrest of assumed cardiac origin. EDTA-blood was drawn during or immediately after termination of cardiopulmonary resuscitation or at hospital admission. Hs-cTnT, copeptin and NT-proBNP were all measured by standardized methods. Patients were classified according to first recorded heart rhythm. Both univariate and multivariate analyses, adjusted for age and gender, were performed using a Cox Proportional-Hazards model. Results: A total of 115 patients were included, 77 patients with VF and 38 patients with asystole as first recorded heart rhythm. Forty-four patients (38,3%) survived to 30-day follow-up. There was no significant difference in hs-cTnT (p = 0.71) or copeptin (p = 0.43) between non-survivors and survivors. The mean NT-proBNP level was significantly elevated in non-survivors compared to survivors, p = 0.001. The hazard ratio (HR) in the univariate analysis for patients with NT-proBNP in the highest quartile (Q4) compared to the lowest quartile (Q1) was 4.68 (95% CI 2.05-10.68), p = < 0.001, and in the multivariate analysis HR was 2.52 (95% CI 0.97-6.53), p = 0.058. All patients in the asystole group died. Only NT-proBNP differed between the two groups, with significantly higher values in the asystole group, p = < 0.001. Conclusion: Applying hs-cTnT, copeptin and NT-proBNP for assessment of prognosis in SCA patients with either VF or asystole, only NT-proBNP was found to yield prognostic information.

• Tveit, Sjur Hansen; Myhre, Peder Langeland; Le, Tri Minh; Seljeflot, Ingebjørg; Høiseth, Arne Didrik & Røsjø, Helge [Show all 7 contributors for this article] (2019). Superiority of high sensitivity cardiac troponin T vs. I for long-term prognostic value in patients with chest pain; data from the Akershus cardiac Examination (ACE) 3 study. Clinical Biochemistry. ISSN 0009-9120. doi: 10.1016/j.clinbiochem.2019.12.016. Full text in Research Archive

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