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.

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.

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. 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. A total of 414 participants (167 [40 Figure developed by the authors using venngage.com with a license to use, reproduce and distribute worldwide. ACE, Akershus Cardiac Examination. BP, blood pressure. DBP, diastolic blood pressure. MRI, magnetic resonance imaging. WMHs, white matter hyperintensities.

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.

Introduction: Secretoneurin (SN) is a novel cardiac biomarker with an upper reference limit of similar to 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.

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.

BACKGROUND:The 2024 European Society of Cardiology (ESC) Guidelines for hypertension introduced the 'elevated BP' (eBP) category (120-139/70-89 mm Hg). Individuals with persistent eBP (130-139/80-89 mm Hg), despite lifestyle intervention, may be recommended pharmacological treatment in case of concomitant elevated cardiovascular (CV) risk. We aimed to assess the impact of these updated recommendations on treatment eligibility at ages 40 and 62-65 and to examine the CV event rates over 30 years of follow-up, focusing on those with eBP (130-139/80-89 mm Hg) eligible for pharmacological treatment. METHODS:Data from individuals born in 1950 who participated in the Age 40 Programme and the Akershus Cardiac Examination 1950 Study was linked to national health registries. These data include BP measurements at age 40 (1990-1991) and 62-65 (2012-2015), assessment of elevated CV risk based on Systematic Coronary Risk Evaluation 2 (SCORE2) and outcomes of major adverse cardiovascular events (MACEs) tracked through 2022. RESULTS:At age 40, 854 (32%) of 2688 individuals had eBP (130-139/80-89 mm Hg), but only 4 had elevated CV risk warranting pharmacological treatment. At age 62-65, 1657 (61%) were on BP-lowering medication or had a BP ≥140/90, while 64 (8%) out of 851 with eBP were eligible for drug treatment. Based on BP values at age 40, only 2 of the 93 MACEs in the eBP (130-139/80-89 mm Hg) category occurred among those eligible for pharmacological treatment. CONCLUSIONS:A single BP measurement at age 40 identified eBP (130-139/80-89 mm Hg) among one-third of the individuals, yet MACE cases within the eBP category occurred primarily in individuals who were not eligible for medical treatment.

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.

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 (beta = 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 (beta = 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

BackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionThe 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.

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.

Introduction:Sleep duration is proposed as a lifestyle-related risk factor for cognitive impairment. We inves-tigated the association between sleep duration andcognitive function in a large population-based cohortaged 62-65 years.Methods:Cross-sectional analysesfrom the Akershus Cardiac Examination 1950 Study.Linear and nonlinear models were conducted to explorethe association between self-reported sleep durationand cognitive function, adjusted for established riskfactors for cognitive impairment.Results:We included3,348 participants, mean age (SD) was 63.9 +/- 0.6 years,48.2% were women, and 47.9% had education>12 years.Mean sleep duration (SD) was 7.0 +/- 1.0 h, and 10.2% hadabnormal sleep duration (<6or>8 h). Individualsreporting<6hor>8hofsleepscoredsignificantly loweron MoCA test and delayed recall trial in adjusted analysis.Conclusions:SleepdurationshowedaninvertedU-shaped association with global cognitive function andmemory, suggesting that both shortened and prolongedsleep are related to adverse brain health.(c) 2024 S. Karger AG, Basel

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.

BACKGROUND:Cardiac troponins (cTns) and biomarkers of inflammation are elevated in heart failure (HF) and predict cardiovascular risk. Whether these biomarkers associate with risk of ventricular arrhythmias (VAs) is unclear. OBJECTIVES:This study sought to assess whether cTnT, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations are associated with incident VA. METHODS:In a prospective, observational study of patients treated with implantable cardioverter-defibrillator, cTnT, GDF-15, IL-6, and CRP were measured at baseline and after 1.4 ± 0.5 years and were associated with implantable cardioverter-defibrillator-detected incident VA, HF hospitalizations, and mortality. RESULTS:This study included 489 patients aged 66 ± 12 years and 83% were men. Median concentrations of cTnT were 15 (Q1-Q3: 9-25) ng/L at inclusion, and higher concentrations were associated with higher age, male sex, diabetes mellitus, coronary artery disease, and HF. During 3.1 ± 0.7 years of follow-up, 137 patients (28%) had ≥1 VA. cTnT concentrations were associated with an increased VA risk (per log-unit, HR: 1.63; 95% CI: 1.31-2.01; P < 0.001), also after adjustment for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction (P < 0.001). GDF-15, IL-6, and CRP concentrations were not associated with incident VA, but all (including cTnT) were associated with HF hospitalization and mortality. Changes in cTnT, GDF-15, IL-6, and CRP from baseline to 1.4 years were not associated with subsequent VA. CONCLUSIONS:Higher concentrations of cTnT, GDF-15, IL-6, and CRP associate with HF hospitalization and death, but only cTnT predict incident VA. These findings suggest that myocardial injury rather than inflammation may play a pathophysiological role in VA and sudden cardiac death.

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.

Abstract Background Ventricular arrhythmia (VA) is a frequent cause of sudden cardiac death (SCD). Treatment to prevent SCD includes device therapy with implantable cardioverter defibrillator (ICD). Although the electrophysiology underlying VA have been described, the molecular understanding of VA risk remains unclear. Purpose To identify proteins that are associated with higher and lower risk of VA. Methods SMASH 1 Study was a prospective observational study of 490 patients treated with ICD. The plasma proteome was analyzed with the Olink Explore 384 Cardiometabolic platform at study inclusion, and patients were followed for mean 3.1± 0.7 years. VA events were defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia registered from ICD recordings and clinical events were recorded from electronic health records. Protein concentrations were quantified relatively as normalized protein expression on a log2-transformed concentrations where a large number represents higher protein level in the sample. Results The mean age was 66±12 years, 83% were male and 51% had a primary prevention ICD-indication. Episode(s) of VA occurred in 137 patients (28%) during follow-up. In total, 353 distinct proteins were successfully analyzed in all patients. Among these, high B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels were associated with a higher risk of VA, while Apolipoprotein M (APOM) was the only protein significantly associated with a lower risk of VA after multiple testing using Benjamini-Hochberg correction (Figure, Panel A). After adjusting for age, sex, body mass index, coronary artery disease, heart failure, renal function, left ventricular ejection fraction and antiarrhythmic medication, only low APOM levels remained significantly associated with VA: HR 0.51 (95%CI 0.32-0.79] per log unit increase, p=0.003. Patients in the lowest quartile of APOM had a particularly high risk of incident VA: HR 2.26 (95%CI 1.60-3.19), p=3.61x10-6, compared to quartile 2-4 (Figure, Panel B). High APOM levels were also associated with a lower risk of HF hospitalizations (HR 0.25 [95%CI 0.16-0.40], p<0.001) and all-cause mortality (HR 0.36 [95%CI 0.22-0.60], p<0.001), and these associations remained significant in adjusted models. Conclusions Low levels of APOM are associated with a greater risk of incident VA, independently of established risk factors. Low APOM also predicted risk of HF hospitalizations and mortality in our cohort, which suggest protective cardiovascular effects of APOM. Figure: Association of individual proteomic measures with risk of ventricular arrhythmias (VA).A:Volcano plots of the associations of individual plasma proteins with incident VA. The dotted line represents the significance level at false discovery rate <0.05 and the red dots are significant proteins after multiple testing using Benjamini-Hochberg correction.B: Risk of VA by quartile of Apolipoprotein M.

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.Trial registration number NCT01555411.

Abstract Background Secretoneurin (SN) is a novel biomarker, which predicts cardiovascular (CV)-related mortality in patients with acute dyspnea and sepsis. Higher SN concentrations have also been found associated with all-cause death in outpatients with heart failure (HF), but whether SN primarily reflects cardiovascular (CV)-related mortality in HF outpatients is not known. Objectives To evaluate the relation between SN concentrations and CV- & non-CV death in ambulatory patients with HF. Methods We studied 184 consecutive patients who attended our HF clinic for routine follow up and had stored blood samples available for SN analysis. SN concentrations were measured with a CE-marked SN ELISA assay. We assessed the associations between SN concentrations and CV & non-CV death. Mortality was ascertained using medical records, autopsy reports and death certificates, and CV deaths included sudden cardiac deaths or mortality due to myocardial infarction, HF or stroke. We assessed association with CV & non-CV death by Kaplan-Meier curves and by Cox proportional hazard regression analysis. Results Median age was 76 years (range: 38-94 years) and two thirds were male. Sixty-three percent had HF with reduced ejection fraction, 22% had NYHA III/IV symptoms and median NT-proBNP was 1079 (interquartile range: 462-2347) ng/L. Median SN level was 60 (range: 21-134) pmol/L. In multivariable linear regression analysis, impaired renal function and lower body-mass index were significantly associated with increasing (log)SN concentration. During median follow up of 540 days, there were 18 CV deaths, including 15 HF deaths, and 7 non-CV deaths. A higher SN concentration was associated with higher risk of CV death, while we did not find statistically significant association between SN concentrations and non-CV deaths (Figure). Patients with SN concentration in the top tertile had 15-fold increased risk of CV death compared to patients with SN concentration in the lowest tertile. In multivariable Cox regression analysis that adjusted for age, NYHA functional class, frailty status, increasing SN concentrations were independently associated with CV death: hazard ratio per logSN (95% CI): 3.01 (1.02-8.90), p=0.04. Conclusion In ambulatory patients with HF, circulating SN concentrations were predictive of CV death. Higher SN concentrations in ambulatory HF patients seemed to be linked to impaired renal function and lower body-mass index. Figure: Kaplan Meier curves illustrating the relation between SN tertiles and (A) CV mortality (B) Non-CV mortality.