Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

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.

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.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

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.

Trajectories of cardiac troponin in the decades before cardiovascular death: a longitudinal cohort study.

BACKGROUND: High-sensitivity cardiac troponin testing is a promising tool for cardiovascular risk prediction, but whether serial testing can dynamically predict risk is uncertain. We evaluated the trajectory of cardiac troponin I in the years prior to a cardiovascular event in the general population, and determine whether serial measurements could track risk within individuals. METHODS: In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on three occasions over a 15-year period. Time trajectories of troponin were constructed in those who died from cardiovascular disease compared to those who survived or died from other causes during follow up and these were externally validated in the HUNT Study. A joint model that adjusts for cardiovascular risk factors was used to estimate risk of cardiovascular death using serial troponin measurements. RESULTS: In 7,293 individuals (mean 58 ± 7 years, 29.4% women) cardiovascular and non-cardiovascular death occurred in 281 (3.9%) and 914 (12.5%) individuals (median follow-up 21.4 years), respectively. Troponin concentrations increased in those dying from cardiovascular disease with a steeper trajectory compared to those surviving or dying from other causes in Whitehall and HUNT (Pinteraction < 0.05 for both). The joint model demonstrated an independent association between temporal evolution of troponin and risk of cardiovascular death (HR per doubling, 1.45, 95% CI,1.33-1.75). CONCLUSIONS: Cardiac troponin I concentrations increased in those dying from cardiovascular disease compared to those surviving or dying from other causes over the preceding decades. Serial cardiac troponin testing in the general population has potential to track future cardiovascular risk.

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.

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.

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.

Pragmatic trials - what are they? / Pragmatiske studier ­ hva er det?

Pragmatic clinical trials are based on data from unselected patients recruited from common clinical practice. These trials therefore bridge the gap between evidence-based medicine and clinical practice.

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.

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.

Temporal Changes in Cardiac Troponin I Are Associated with Risk of Cardiovascular Events in the General Population: The Nord-Trøndelag Health Study.

BACKGROUND: Cardiac troponins are associated with cardiovascular risk in the general population, but whether temporal changes in cardiac troponin I provide independent prognostic information remains uncertain. Using a large community-based cohort with follow-up close to the present day, we aimed to investigate the associations between temporal changes in cardiac troponin and cardiovascular events. METHODS: We measured cardiac troponin I with a high-sensitivity assay (hs-cTnI) in 4805 participants attending both the second (HUNT 2, 1995-97) and third wave (HUNT 3, 2006-2008) of the prospective observational Nord-Trøndelag Health (HUNT) Study. We constructed statistical models with both relative and absolute changes of hs-cTnI from HUNT 2 to HUNT 3. A composite end point of cardiovascular death or first admission for myocardial infarction or heart failure was generated. RESULTS: Participants with relative decrease in hs-cTnI were more frequently younger and female and had lower blood pressure and body mass index. Participants with relative increase in hs-cTnI more frequently were older and male, with higher systolic blood pressure. The adjusted hazard ratio (HR) for relative increase in hs-cTnI was 1.68 (95% CI, 1.16-2.42) and the adjusted HR for relative decrease was 1.19 (95% CI, 0.84-1.68). Absolute increases in hs-cTnI exhibited similar prognostic properties as relative increases in hs-cTnI. The most recent measurement of hs-cTnI outperformed the change variables in discrimination and reclassification models. CONCLUSIONS: Both relative and absolute increases in hs-cTnI are independently associated with cardiovascular risk. For refinement of risk prediction models, the most recent measurement of hs-cTnI should be preferred in clinical practice.

Prognostic and diagnostic significance of mid-regional pro-atrial natriuretic peptide in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 Study.

PURPOSE: To compare the diagnostic and prognostic value of mid-regional pro-ANP (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea. METHODS: MR-proANP and NT-proBNP were measured with commercial immunoassays at hospital admission (n = 313), on day 2 (n = 234), and before discharge (n = 91) and compared for diagnosing acute heart failure (HF; n = 143) and to predict mortality among patients with acute HF and acute exacerbation of chronic obstructive pulmonary disease (AECOPD; n = 84) separately. RESULTS: The correlation coefficient between MR-proANP and NT-proBNP was 0.89 (p < 0.001) and the receiver-operating area under the curve (AUC) was 0.85 (95% CI 0.81-0.89) for MR-proANP and 0.86 (0.82-0.90) for NT-proBNP to diagnose acute HF. During a median follow-up of 816 days, mortality rates were 46% in acute HF patients and 42% in AECOPD patients. After adjustment for other risk variables by multivariate Cox regression analysis, MR-proANP and NT-proBNP concentrations were associated with mortality in patients with acute HF, but only MR-proANP were associated with mortality among patients with AECOPD: hazard ratio (lnMR-proANP) 1.98 (95% CI 1.17-3.34). CONCLUSION: MR-proANP and NT-proBNP concentrations provide similar diagnostic and prognostic information in patients with acute HF. In contrast to NT-proBNP, MR-proANP measurements also provided independent prognostic information in AECOPD patients.