Reference intervals of circulating secretoneurin concentrations determined in a large cohort of community dwellers: the HUNT study.

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.

Trans-Cardiac Gradient of Secretoneurin in Patients with Takotsubo Syndrome.

INTRODUCTION: Secretoneurin (SN) is a novel biomarker that provides prognostic information in patients with cardiovascular disease. In experimental models, SN production is increased in the failing myocardium. Currently, no information is available on SN production in human myocardium. Accordingly, we wanted to determine the trans-cardiac gradient of SN in patients with Takotsubo syndrome (TTS), and to correlate circulating SN concentrations with indices of cardiac structure and function. METHODS: We included 15 women diagnosed with TTS according to established criteria. Plasma SN concentrations were measured in blood samples obtained simultaneously from the aortic root and the coronary sinus. Coronary physiology was assessed by invasive measurements, and we used cardiac magnetic resonance imaging to determine left ventricular ejection fraction (LVEF) and cardiac mass. RESULTS: Median age was 65 years and median LVEF was 45%. Median SN concentration was 39 (25th-75th percentile 31-44) pmol/L in the coronary sinus and 37 (30-41) pmol/L in the aortic root (p = 0.02 for difference). SN concentrations in the aortic root showed the highest correlations with N-terminal B-type natriuretic peptide (rho = 0.47) and estimated glomerular filtration rate (rho = -0.41). In contrast, we found weak correlations between SN concentrations and index of myocardial resistance (rho = 0.12), LVEF (rho = 0.08), and cardiac mass (rho = -0.09). CONCLUSION: We demonstrate a positive trans-cardiac gradient of SN in patients with TTS, which supports the hypothesis that SN is produced and released in the human myocardium in situations of myocardial dysfunction and stress.

Left atrial function in middle-aged men and women with and without paroxysmal atrial fibrillation: Data from the Akershus Cardiac Examination (ACE) 1950 study.

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.

Genome-wide association study of cardiac troponin I in the general population.

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.

Serial blood pressure measurements, left ventricular remodelling and cardiovascular outcomes.

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.

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.

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 <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.

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.

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 ß-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.

Lifetime obesity trends are associated with subclinical myocardial injury: The Trøndelag health study.

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.

QRS fragmentation is associated with increased risk of ventricular arrhythmias in high-risk patients; Data from the SMASH 1 Study.

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.

Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown. METHODS: Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers. RESULTS: Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P<0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, P<0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (P<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, P<0.001). CONCLUSIONS: GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.

Cardiac pathology 6 months after hospitalization for COVID-19 and association with the acute disease severity.

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.

Circulating MicroRNA-210 Concentrations in Patients with Acute Heart Failure: Data from the Akershus Cardiac Examination 2 Study.

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.

B-Type Natriuretic Peptide Is Associated with Indices of Left Ventricular Dysfunction in Healthy Subjects from the General Population: The Akershus Cardiac Examination 1950 Study.

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.

Insomnia symptoms and subclinical myocardial injury: Data from the Nord-Trøndelag Health (HUNT) study.

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 (ß 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.

Performance of a Novel Research-Use-Only Secretoneurin ELISA in Patients with Suspected Acute Coronary Syndrome: Comparison with an Established Secretoneurin Radioimmunoassay.

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.

Cardiac Troponin I and T Are Associated with Left Ventricular Function and Structure: Data from the Akershus Cardiac Examination 1950 Study.

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 < 0.001), and correlated moderately (r = 0.53; P < 0.001). cTnI was more strongly associated with male sex (P = 0.018), higher education (P < 0.001), history of hypertension (P < 0.001), and age (P < 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.

Plasma marine n-3 polyunsaturated fatty acids and cardiovascular risk factors: data from the ACE 1950 study.

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.ß-coeff.) - 0.14, p < 0.001], body mass index (Std. ß-coeff. -0.08, p < 0.001), serum creatinine (Std. ß-coeff. -0.03, p = 0.05), C-reactive protein levels (Std. ß-coeff. - 0.03, p = 0.04), higher levels of serum high-density lipoprotein cholesterol (Std. ß-coeff. 0.08, p < 0.001) and low-density lipoprotein cholesterol (Std. ß-coeff. 0.04, p = 0.003). High levels of plasma marine n-3 PUFAs were also associated with lower glycated hemoglobin (Std. ß-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.

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.

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. TRIAL REGISTRATION: ClinicalTrials. gov, NCT02886273 .

Novel biomarkers of cardiovascular disease: Applications in clinical practice.

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.

Circulating Secretoneurin Concentrations After Cardiac Surgery: Data From the FINNish Acute Kidney Injury Heart Study.

OBJECTIVES: Secretoneurin is associated with cardiomyocyte Ca handling and improves risk prediction in patients with acute myocardial dysfunction. Whether secretoneurin improves risk assessment on top of established cardiac biomarkers and European System for Cardiac Operative Risk Evaluation II in patients undergoing cardiac surgery is not known. DESIGN: Prospective, observational, single-center sub-study of a multicenter study. SETTING: Prospective observational study of survival in patients undergoing cardiac surgery. PATIENTS: A total of 619 patients undergoing cardiac surgery. INTERVENTIONS: Patients underwent either isolated coronary artery bypass graft surgery, single noncoronary artery bypass graft surgery, two procedures, or three or more procedures. Procedures other than coronary artery bypass graft were valve surgery, surgery on thoracic aorta, and other cardiac surgery. MEASUREMENTS AND MAIN RESULTS: We measured preoperative and postoperative secretoneurin concentrations and adjusted for European System for Cardiac Operative Risk Evaluation II, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T concentrations in multivariate analyses. During 961 days of follow-up, 59 patients died (9.5%). Secretoneurin concentrations were higher among nonsurvivors compared with survivors, both before (168 pmol/L [quartile 1-3, 147-206 pmol/L] vs 160 pmol/L [131-193 pmol/L]; p = 0.039) and after cardiac surgery (173 pmol/L [129-217 pmol/L] vs 143 pmol/L [111-173 pmol/L]; p < 0.001). Secretoneurin concentrations decreased from preoperative to postoperative measurements in survivors, whereas we observed no significant decrease in secretoneurin concentrations among nonsurvivors. Secretoneurin concentrations were weakly correlated with established risk indices. Patients with the highest postoperative secretoneurin concentrations had worse outcome compared with patients with lower secretoneurin concentrations (p < 0.001 by the log-rank test) and postoperative secretoneurin concentrations were associated with time to death in multivariate Cox regression analysis: hazard ratio lnsecretoneurin 2.96 (95% CI, 1.46-5.99; p = 0.003). Adding postoperative secretoneurin concentrations to European System for Cardiac Operative Risk Evaluation II improved patient risk stratification, as assessed by the integrated discrimination index: 0.023 (95% CI, 0.0043-0.041; p = 0.016). CONCLUSIONS: Circulating postoperative secretoneurin concentrations provide incremental prognostic information to established risk indices in patients undergoing cardiac surgery.