Insomnia symptoms and risk of bloodstream infections: prospective data from the prospective population-based Nord-Trøndelag Health Study (HUNT), Norway.

Previous research suggests decreased immune function and increased risk of infections in individuals with insomnia. We examined the effect of insomnia symptoms on risk of bloodstream infections (BSIs) and BSI-related mortality in a population-based prospective study. A total of 53,536 participants in the second Norwegian Nord-Trøndelag Health Study (HUNT2) (1995-97) were linked to prospective data on clinically relevant BSIs until 2011. In Cox regression, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for a first-time BSI and for BSI-related mortality (BSI registered ≤30 days prior to death) associated with insomnia symptoms. Compared with participants who reported "no symptoms", participants reporting having "difficulty initiating sleep" (DIS) often/almost every night had a HR for a first-time BSI of 1.14 (95% CI 0.96-1.34). Participants reporting "difficulties maintaining sleep" (DMS) often/almost every night had a HR of 1.19 (95% CI 1.01-1.40), whereas those having a feeling of "non-restorative sleep" once a week or more had a HR of 1.23 (95% CI 1.04-1.46). Participants frequently experiencing all three of the above symptoms had a HR of 1.39 (1.04-1.87), whilst those who had both DIS and DMS had a HR of 1.15 (0.93-1.41) and being troubled by insomnia symptoms to a degree that affected work performance was associated with a HR of 1.41 (95% CI 1.08-1.84). The HRs for BSI-related mortality suggest an increased risk with increasing insomnia symptoms, but the CIs are wide and inconclusive. We found that frequent insomnia symptoms and insomnia symptoms that affected work performance were associated with a weak positive increased risk of BSI.

Bone mineral density and risk of cardiovascular disease in men and women: the HUNT study.

The association between bone mineral density (BMD) and cardiovascular disease (CVD) is not fully understood. We evaluated BMD as a risk factor for cardiovascular disease and specifically atrial fibrillation (AF), acute myocardial infarction (AMI), ischemic (IS) and hemorrhagic stroke (HS) and heart failure (HF) in men and women. This prospective population cohort utilized data on 22 857 adults from the second and third surveys of the HUNT Study in Norway free from CVD at baseline. BMD was measured using single and dual-energy X-ray absorptiometry in the non-dominant distal forearm and T-score was calculated. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from adjusted cox proportional hazards models. The analyses were sex-stratified, and models were adjusted for age, age-squared, BMI, physical activity, smoking status, alcohol use, and education level. Additionally, in women, we adjusted for estrogen use and postmenopause. During a mean follow-up of 13.6 ± 5.7 years, 2 928 individuals (12.8%) developed fatal or non-fatal CVD, 1 020 AF (4.5%), 1 172 AMI (5.1%), 1 389 IS (6.1%), 264 HS (1.1%), and 464 HF (2.0%). For every 1 unit decrease in BMD T-score the HR for any CVD was 1.01 (95% CI 0.98 to 1.04) in women and 0.99 (95% CI 0.94 to 1.03) in men. Point estimates for the four cardiovascular outcomes ranged from slightly protective (HR 0.95 for AF in men) to slightly deleterious (HR 1.12 for HS in men). We found no evidence of association of lower distal forearm BMD with CVD, AF, AMI, IS, HS, and HF.

Weight and weight change and risk of atrial fibrillation: the HUNT study.

AIMS: Although obesity has been associated with risk of atrial fibrillation (AF), the associations of long-term obesity, recent obesity, and weight change with AF risk throughout adulthood are uncertain. METHODS AND RESULTS: An ambispective cohort study was conducted which included 15 214 individuals. The cohort was created from 2006 to 2008 (the baseline) and was followed for incident AF until 2015. Weight and height were directly measured at baseline. Data on previous weight and height were retrieved retrospectively from measurements conducted 10, 20, and 40 years prior to baseline. Average body mass index (BMI) over time and weight change was calculated. During follow-up, 1149 participants developed AF. The multivariable-adjusted hazard ratios were 1.2 (95% confidence interval 1.0-1.4) for average BMI 25.0-29.9 kg/m2 and 1.6 (1.2-2.0) for average BMI ≥30 kg/m2 when compared with normal weight. The association of average BMI with AF risk was only slightly attenuated after adjustment for most recent BMI. In contrast, current BMI was not strongly associated with the risk of AF after adjustment for average BMI earlier in life. Compared with stable BMI, both loss and gain in BMI were associated with increased AF risk. After adjustment for most recent BMI, the association of BMI gain with AF risk was largely unchanged, while the association of BMI loss with AF risk was weakened. CONCLUSION: Long-term obesity and BMI change are associated with AF risk. Obesity earlier in life and weight gain over time exert cumulative effects on AF development even after accounting for most recent BMI.

Asthma, asthma control and risk of acute myocardial infarction: HUNT study.

Asthma, a chronic inflammatory airway disease, shares several common pathophysiological mechanisms with acute myocardial infarction (AMI). Our aim was to assess the prospective associations between asthma, levels of asthma control and risk of AMI. We followed 57,104 adults without previous history of AMI at baseline from Nord-Trøndelag health study (HUNT) in Norway. Self-reported asthma was categorised as active asthma (i.e., using asthma medication) and non-active asthma (i.e., not using asthma medication). Levels of asthma control were defined as controlled, partly controlled, and uncontrolled based on the Global Initiative for Asthma guidelines. AMI was ascertained by linking HUNT data with hospital records. A total of 2868 AMI events (5.0%) occurred during a mean (SD) follow-up of 17.2 (5.4) years. Adults with active asthma had an estimated 29% higher risk of developing AMI [adjusted hazard ratio (HR) 1.29, 95% CI 1.08-1.54] compared with adults without asthma. There was a significant dose-response association between asthma control and AMI risk, with highest risk in adults with uncontrolled asthma (adjusted HR 1.73, 95% CI 1.13-2.66) compared to adults with controlled asthma (p for trend < 0.05). The associations were not explained by smoking status, physical activity and C-reactive protein levels. Our study suggests that active asthma and poor asthma control are associated with moderately increased risk of AMI. Further studies are needed to evaluate causal relationship and the underlying mechanisms and to clarify the role of asthma medications in the risk of AMI.

Associations of Insomnia Symptoms With Blood Pressure and Resting Heart Rate: The HUNT Study in Norway.

OBJECTIVE: Although elevated heart rate and blood pressure might represent biologically plausible links for the association of insomnia symptoms with increased risk of cardiovascular disease (CVD), few large studies have investigated the associations of insomnia symptoms with these factors. Our aim was to investigate the associations of self-reported insomnia symptoms with systolic and diastolic blood pressure and resting heart rate in a large population-based study. PARTICIPANTS: Self-reported information on insomnia symptoms, including sleep initiation problems, frequent awakening and early awakenings during night, and measurements of resting heart rate and blood pressure were collected from a total of 50,806 men and women who participated in the third wave of the Nord-Trøndelag Health Study (HUNT-3) in 2006-2008. METHODS: In multivariable analyses, we adjusted for sociodemographic factors, lifestyle factors, established CVD risk factors, and snoring or breathing pauses. RESULTS: Compared to participants reporting none of the insomnia symptoms, those having all three insomnia symptoms several times a week had lower diastolic blood pressure (-0.80 [95% CI: -1.47 to -0.14] mmHg, p = 0.02), lower systolic blood (-1.69 [95% CI: -2.76 to -0.63) mmHg, p < 0.001), and higher resting heart rate (0.83 [95% CI: 0.11 to 1.55] beats/minute, p = 0.02). CONCLUSIONS: We found a modest positive association of insomnia symptoms with resting heart rate, and a modest inverse association of insomnia with blood pressure. However, the actual differences were small, and likely of less clinical importance. Prospective studies are needed to establish whether the potential link between insomnia and CVD is mediated through changes in heart rate and/or blood pressure.

Insomnia and left ventricular function - an echocardiography study.

OBJECTIVES: Recently, studies have reported an association of insomnia with incident heart failure but its causal relation is still uncertain. In patients with heart failure, the left ventricular function is impaired and the deterioration may start long before the patient experiences any symptoms. As the first study, we examined the association of insomnia with left ventricular function using state-of-the art echocardiography methods. DESIGN: In the echocardiography study, several indices of left ventricular function were examined in participants free from cardiovascular diseases, hypertension and diabetes. In total 788 participants with information on all relevant covariates were included. We calculated the least square mean of indices of left ventricular function associated with increasing number of insomnia symptoms (i.e. difficulties falling asleep, frequent awakenings and early awakenings), including systolic mitral annular excursion, peak velocities of systolic and diastolic motion of the mitral annulus and systolic deformation of the left ventricle. RESULTS: We found no clear evidence that increasing number of insomnia symptoms is associated with any of the left ventricular function indices. CONCLUSIONS: The methods that were used are sensitive to detect preclinical HF, and therefore, our findings do not support a causal relation between insomnia symptoms and HF.

Insomnia and the risk of incident heart failure: a population study.

AIMS: Insomnia is highly prevalent among heart failure patients, but only a few small studies have investigated insomnia symptoms and risk of heart failure. We aimed to assess the prospective association between self-reported insomnia symptoms and the risk of incident heart failure in a large Norwegian cohort. METHODS AND RESULTS: Baseline data on insomnia symptoms, including difficulty initiating sleep, difficulty maintaining sleep and having non-restorative sleep, socio-demographic variables, and health status, including established cardiovascular risk factors, were collected from 54 279 men and women 20-89 years of age who participated in the Nord-Trøndelag Health study (HUNT) between 1995 and 1997 and were free from known heart failure at baseline. The cohort was followed for incident heart failure from baseline through 2008. We used Cox proportional hazard models to assess the association of baseline insomnia symptoms with the risk of heart failure. A total of 1412 cases of heart failure occurred during a mean follow-up of 11.3 years (SD = 2.9 years), either identified at hospitals or by the National Cause of Death Registry. There was a dose-dependent association between the number of insomnia symptoms and risk of heart failure. The multi-adjusted hazard ratios were 0.96 (0.57-1.61), 1.35 (0.72-2.50), and 4.53 (1.99-10.31) for people with one, two, and three insomnia symptoms, compared with people with none of the symptoms (P for trend 0.021). CONCLUSIONS: Insomnia is associated with an increased risk of incident heart failure. If our results are confirmed by others and causation is proved, evaluation of insomnia symptoms might have consequences for cardiovascular prevention.

Insomnia and the risk of acute myocardial infarction: a population study.

BACKGROUND: Few prospective studies have investigated insomnia in relation to risk for coronary heart disease. We assessed insomnia symptoms and risk of acute myocardial infarction (AMI) in a large, population-based study. METHODS AND RESULTS: A total of 52 610 men and women were followed up for a first AMI, and 2368 incident AMIs occurred during 11.4 years of follow-up, either identified at hospitals or by the National Cause of Death Registry. In our analyses, we adjusted for age, sex, marital status, education, shift work, blood pressure, lipids, diabetes mellitus, body mass index, physical activity, smoking, and alcohol consumption. Difficulties initiating and maintaining sleep and having a feeling of nonrestorative sleep were associated with a moderate increase in AMI risk. The multiadjusted hazard ratios for AMI were 1.45 (95% confidence interval 1.18-1.80) for people with difficulties initiating sleep almost every night, 1.30 (1.01-1.68) for those with difficulties maintaining sleep almost every night, and 1.27 (1.03-1.57) for those with a feeling of nonrestorative sleep more than once a week compared with people who never experienced these sleep difficulties. When we combined the symptoms, a dose-dependent association was seen between the number of insomnia symptoms and AMI risk (P for trend 0.003). Alternative multivariable models and different sensitivity analyses suggest that the results were robust, especially concerning difficulties initiating sleep. CONCLUSIONS: Insomnia is associated with a moderately increased risk for AMI.

Mortality from ischaemic heart disease: sex-specific effects of transferrin saturation, serum iron, and total iron binding capacity. The HUNT study.

BACKGROUND: We assessed sex-specific associations of iron status with ischaemic heart disease (IHD) mortality and explored whether the strength of the associations changed during follow-up. DESIGN: Prospective cohort study. METHODS: During 11.4 years of follow-up, IHD mortality was studied in 28,154 men and 32,644 women without known myocardial infarction or stroke at baseline. RESULTS: During follow-up, 1,034 men and women died from IHD. Compared to being in the highest quartile of transferrin saturation, the multivariate adjusted hazard ratio associated with being in the lowest quartile was 1.3 (95% CI 1.0-1.6) in men and 1.4 (95% CI 1.0-1.9) in women. The corresponding hazard ratios for serum iron were 1.5 (95% CI 1.1-1.9) in men and 1.1 (95% CI 0.8-1.4) in women, and for total iron binding capacity (TIBC), the hazard ratio of being in the highest compared to the lowest quartile was 0.9 (95% CI 0.8-1.2) in men and 1.5 (95% CI 1.1-2.0) in women. Associations with iron status were stronger in the early than in later stages of follow-up. CONCLUSIONS: The results suggest that low iron status may be a late sign of IHD pathology or that unknown prevalent disease at baseline could influence the associations.

Symptoms of anxiety and depression and risk of atrial fibrillation-The HUNT study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Anxiety and depression may activate the autonomic nervous system which is likely to play an important role in the etiology of AF. However, little is known about the association between symptoms of anxiety and depression and risk of AF. OBJECTIVE: This study aimed to assess the association between symptoms of anxiety and depression and risk of AF. METHODS: In a population-based study, 37,402 adult residents were followed for incident AF from 2006 to 2008 until 2015. Participants were classified according to data on anxiety and depression symptoms. Cox proportional regression models were used to adjust for common AF risk factors. RESULTS: During a median follow-up of 8.1 years, 1433 (3.8%) participants developed AF. In comparisons with no anxiety symptoms, the multivariable-adjusted hazard ratios (HRs) were 1.1 (95% CI: 0.9-1.5) for mild to moderate anxiety symptoms and 1.0 (95% CI: 0.8-1.4) for severe anxiety symptoms. In comparisons with no depression symptoms, the multivariable-adjusted HRs were 1.5 (95% CI: 1.2-1.8) for mild to moderate depression symptoms and 0.9 (95% CI: 0.6-1.3) for severe depression symptoms. Recurrent anxiety/depression symptoms were not associated with increased AF risk. CONCLUSIONS: In this large, population-based study, we found no evidence of an association between symptoms of anxiety or severe depression and AF risk, even for recurrent anxiety or depression symptoms. An unexpected association of symptoms of mild to moderate depression with increased AF risk requires confirmation in other studies. Our findings add to the sparse literature on symptoms of anxiety and depression and risk of AF.

Metabolically Healthy Obesity and Risk for Atrial Fibrillation: The HUNT Study.

OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia and has been described as a global epidemic. Although AF is associated with both obesity and its metabolic consequences, little is known about the association between metabolically healthy obesity and AF. METHODS: In a population-based study, 47,870 adults were followed for incident AF from 2006 to 2008 until 2015. Participants were classified according to BMI and metabolic status (using waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure, and glucose) at baseline. RESULTS: During a median follow-up of 8.1 years, 1,758 participants developed AF. Compared with metabolically healthy individuals with BMI < 25 kg/m2 , the multivariable-adjusted hazard ratios for metabolically healthy and unhealthy obesity were 1.6 (95% CI: 1.2 to 2.1) and 1.6 (95% CI: 1.3 to 1.9), respectively. AF risk increased according to the severity of obesity. CONCLUSIONS: Metabolically healthy and unhealthy obesity increased AF risk to a similar extent. Severity of obesity was positively associated with AF risk regardless of metabolic status.

Associations of Asthma and Asthma Control With Atrial Fibrillation Risk: Results From the Nord-Trøndelag Health Study (HUNT).

Importance: Asthma, a chronic inflammatory airway disease, and atrial fibrillation (AF) share several common pathophysiological mechanisms. Research on the association between asthma and atrial fibrillation is lacking, and to our knowledge, no previous studies have assessed the dose-response association between levels of asthma control and AF. Objective: To assess the association between asthma, levels of asthma control, and AF. Design, Setting, and Participants: This prospective population cohort analyzed data on adults from a second and third iteration of the survey-based Nord-Trøndelag Health Study (HUNT) in Norway. All included participants were free from AF at baseline. Atrial fibrillation was ascertained by linking HUNT data with hospital records from the 2 hospitals in Nord-Trøndelag County. Data analysis was completed from May 2017 to November 2017. Exposures: Self-reported asthma was categorized into 3 groups: those who had ever had asthma, those who self-report being diagnosed with asthma, and those who had active asthma. Asthma control was defined according to Global Initiative for Asthma guidelines and was categorized into controlled, partly controlled, and uncontrolled cases. Main Outcomes and Measures: Atrial fibrillation. Results: A total of 54 567 adults were included (of whom 28 821 [52.8%] were women). Of these, 5961 participants (10.9%) reported ever having asthma, 3934 participants (7.2%) reported being diagnosed with asthma, and 2485 participants (4.6%) reported having active asthma. During a mean (SD) follow-up of 15.4 (5.8) years, 2071 participants (3.8%) developed AF. Participants with physician-diagnosed asthma had an estimated 38% higher risk of developing AF (adjusted hazard ratio, 1.38 [95% CI, 1.18-1.61]) compared with participants without asthma. There was a dose-response association between levels of asthma control and risk of AF with the highest risk for AF in participants with uncontrolled asthma (adjusted hazard ratio, 1.74 [95% CI, 1.26-2.42]; P for trend < .001). Conclusions and Relevance: Asthma and lack of asthma control were associated with moderately increased risks of AF in a dose-response manner. Further studies are needed to explore the underlying mechanisms and clarify causal pathways between asthma and AF.

Extracellular matrix markers and risk of myocardial infarction: The HUNT Study in Norway.

Aims Extracellular matrix remodelling may influence atherosclerotic progression and plaque stability. We hypothesized that evaluation of extracellular matrix markers, with potentially different roles during atherogenesis, could provide information on underlying mechanisms and risk of myocardial infarction (MI) in apparently healthy individuals. Methods We conducted a case-control study nested within the population-based HUNT2 cohort in Norway. A total of 58,761 men and women, free of known cardiovascular disease, were followed for a first MI. During 11.3 years of follow-up, 1587 incident MIs were registered, and these cases were compared with 3959 age- and sex-matched controls. Circulating levels of the ECM proteins CD147 (ECM metalloproteinase inducer; EMMPRIN), cartilage oligomeric matrix protein (COMP: thrombospondin-5) and YKL-40 (chitinase-3-like-1) were measured by enzyme immunoassays. Results We found an inverse association between COMP (quartile (Q) 4 vs. Q1: hazard ratio 0.81 (95% confidence interval: 0.67-0.98)) and YKL-40 (Q4 vs. Q1: hazard ratio 0.77 (0.62-0.95)) with incidence of MI after full multivariable adjustment. Serum CD147 was not associated with MI risk in adjusted analysis. Conclusion High levels of COMP and YKL-40 were associated with lower risk of incident MI, suggesting a potential beneficial role in promoting plaque stability in individuals without incident cardiovascular disease.

Monocyte/macrophage and T cell activation markers are not independently associated with MI risk in healthy individuals - results from the HUNT Study.

BACKGROUND: We hypothesized that circulating markers reflecting monocyte/macrophage and T cell activation are associated with increased risk of myocardial infarction (MI) in apparently healthy individuals. METHODS: Serum monocyte/macrophage and T cell activation markers soluble (s) CD163, sCD14, Gal3BP, sCD25 and sCD166 were analyzed by enzyme-immunoassay in a case-control study nested within the population-based HUNT2 cohort in Norway. Among 58,761 apparently healthy men and women followed a median 11.3years, 1587 incident MI cases were registered, and compared to 3959 age- and sex-matched controls. RESULTS: Higher serum sCD163 (Q4 vs. Q1 OR: 1.27, P-trend 0.002), sCD14 (Q4 vs. Q1 OR: 1.38, P-trend<0.001), and especially sCD25 (Q4 vs. Q1 OR: 1.45, P-trend<0.001), were associated with increased MI risk in the age-and sex adjusted models. However, after additional adjustment for cardiovascular risk factors these associations were strongly attenuated (Q4 vs Q1 ORs between 1.02 and 1.12, P-trends between 0.30 and 0.58). CONCLUSIONS: sCD163, sCD14 and sCD25 may reflect leukocyte activation and inflammatory mechanisms related to atherogenesis, but do not predict MI risk above and beyond conventional cardiovascular risk factors.

Light-to-moderate drinking and incident heart failure--the Norwegian HUNT study.

BACKGROUND: We analyzed the association between light-to-moderate alcohol intake and the risk of heart failure (HF). METHODS AND RESULTS: We studied 60,665 individuals free of HF who provided information on alcohol consumption in a population-based cohort study conducted in 1995-97 in Norway. Sociodemographic factors, cardiovascular risk factors and common chronic disorders were assessed by questionnaires and/or by a clinical examination. The cohort was followed for a first HF event for an average of 11.2 ± 3.0 years. Mean alcohol consumption was 2.95 ± 4.5 g/day; 1588 HF cases occurred during follow-up. The quantity of alcohol consumption was inversely associated with incident HF in this low-drinking population. The risk was lowest for consumption over three but less than six drinks/week; the multivariate hazard ratio when comparing this category to non-drinkers was 0.67 (95% CI: 0.50-0.92). Among problem drinkers based on CAGE questionnaires, total consumption showed no favorable association with HF, even when overall consumption was otherwise moderate. Excluding former drinkers and controlling for common chronic diseases had minimal effect on these associations. Frequent alcohol consumption, i.e. more than five times/month, was associated with the lowest HF risk; the adjusted hazard ratio comparing this group to alcohol intake less than once/month was 0.83 (95% CI: 0.68-1.03). We found no evidence for a differential effect according to beverage type, nor that the competing risks of death from other causes modified the association. CONCLUSIONS: Frequent light-to-moderate alcohol consumption without problem drinking was associated with a lower HF risk in this population characterized by a low average alcohol intake.

Soluble CXCL16 and risk of myocardial infarction: The HUNT study in Norway.

BACKGROUND AND AIMS: CXCL16 is an interferon-γ-regulated chemokine and scavenger receptor for oxidized low-density lipoprotein that is expressed in atherosclerotic lesions. High soluble CXCL16 levels during acute cardiovascular events may indicate impaired long-term prognosis, but it is not known if CXCL16 is associated with the risk of developing cardiovascular disease in healthy individuals. We aimed to assess whether soluble CXCL16 is associated with risk of myocardial infarction (MI) in a nested case-control study within a large population-based cohort. METHODS: We conducted a case-control study nested within the population-based HUNT2 cohort in Norway. A total of 58,761 men and women free of known cardiovascular disease were followed for a first myocardial infarction (MI), and during 11.3 years of follow-up, 1587 incident MIs were registered. These cases were compared to 3959 age- and sex-matched controls. RESULTS: Among MI cases, the median CXCL16 concentration was 9.9 ng/ml (interquartile range 7.2-12.6) compared to 9.6 ng/ml (interquartile range 6.9-12.3) among controls (p < 0.001). Although the difference in median value between cases and controls was small, MI risk was twice as high (OR, 2.08; 95% CI: 1.74-2.50) among participants in the highest quartile compared to participants in the lowest quartile of CXCL16 after adjustment for age and sex. Additional adjustment for serum lipids, body mass index, smoking habits, diabetes mellitus, serum creatinine, and high-sensitivity C-reactive protein attenuated the excess risk by about half, yielding an odds ratio of 1.46 (95% CI: 1.19-1.79). CONCLUSION: Soluble CXCL16 may provide novel information in clinical cardiovascular risk assessment, but its importance needs to be verified in other prospective population studies.

Circulating PCSK9 and Risk of Myocardial Infarction: The HUNT Study in Norway.

The usefulness of circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) as a risk marker of coronary heart disease in the general population remains unclear. In a nested case-control study in Norway, 1,488 incident myocardial infarctions were registered during 11.3 years of follow-up and compared with 3,819 controls. Compared with participants in the lowest quartile of PCSK9, myocardial infarction risk was 47% higher in the highest quartile after adjustment for age and sex. After additional adjustment for low-density lipoprotein cholesterol, the association was strongly attenuated. Thus, circulating PCSK9 does not contribute useful information in the assessment of myocardial infarction risk in the general population beyond the information provided by lipid measurements.

Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.

BACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993. RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048). CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.

Symptoms of anxiety and depression and risk of heart failure: the HUNT Study.

AIMS: Symptoms of anxiety and depression often co-exist with cardiovascular disease, yet little is known about the prospective risk for heart failure (HF) in people with symptoms of depression and anxiety. We aimed to study these prospective associations using self-reported symptoms of anxiety, depression, and mixed symptoms of anxiety and depression (MSAD) in a large population sample. METHODS AND RESULTS: In the second wave of the Nord-Trøndelag Health Study (HUNT 2, 1995-1997), Norway, baseline data on symptoms of anxiety and depression, socio-demographic variables, health status including cardiovascular risk factors, and common chronic somatic diseases were registered for 62,567 adults, men and women, free of known HF. The cohort was followed for incident HF from baseline throughout 2008. A total of 1499 cases of HF occurred during a mean follow-up of 11.3 years (SD = 2.9), identified either in hospital registers or by the National Cause of Death Registry. There was no excess risk for future HF associated with symptoms of anxiety or MSAD at baseline. For depression, the multi-adjusted hazard ratios for HF were 1.07 (0.87-1.30) for moderate symptoms and 1.41 (1.07-1.87) for severe symptoms (P for trend 0.026). Established cardiovascular risk factors, acute myocardial infarction (AMI) prior to baseline, and adjustment for incident AMI as a time-dependent covariate during follow-up had little influence on the estimates. CONCLUSION: Symptoms of depression, but not symptoms of anxiety or MSAD, were associated with increased risk for HF in a dose-response manner. The increased risk could not be fully explained by cardiovascular or socio-economic risk factors, or by co-morbid AMI.

Risk of myocardial infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-Trøndelag Health Study), Norway.

OBJECTIVES: This study sought to investigate whether obesity in the absence of metabolic abnormalities might be a relatively benign condition in relation to acute myocardial infarction (AMI) and heart failure (HF). BACKGROUND: The results of previous studies are conflicting for AMI and largely unknown for HF, and the role of the duration of obesity has not been investigated. METHODS: In a population-based prospective cohort study, a total of 61,299 men and women free of cardiovascular disease were classified according to body mass index (BMI) and metabolic status at baseline. BMI also was measured 10 and 30 years before baseline for 27,196 participants. RESULTS: During 12 years of follow-up, 2,547 participants had a first AMI, and 1,201 participants had a first HF. Compared with being normal weight (BMI <25 kg/m(2)) and metabolically healthy, the multivariable-adjusted hazard ratio (HR) for AMI was 1.1 (95% confidence interval [CI]: 0.9 to 1.4) among obese (BMI ≥30 kg/m(2)) and metabolically healthy participants and 2.0 (95% CI: 1.7 to 2.3) among obese and metabolically unhealthy participants. We found similar results for severe (BMI ≥35 kg/m(2)), long-lasting (>30 years), and abdominal obesity stratified for metabolic status. For HF, the HRs associated with obesity were 1.7 (95% CI: 1.3 to 2.3) and 1.7 (95% CI: 1.4 to 2.2) for metabolically healthy and unhealthy participants, respectively. Severe and long-lasting obesity were particularly harmful in relation to HF, regardless of metabolic status. CONCLUSIONS: In relation to AMI, obesity without metabolic abnormalities did not confer substantial excess risk, not even for severe or long-lasting obesity. For HF, even metabolically healthy obesity was associated with increased risk, particularly for long-lasting or severe obesity.