Development of a tool to predict the risk of incident heart failure in a general population: the HUNT for HF risk score.

AIMS: Currently, no incident heart failure (HF) risk score that is in regular use in a general population is available. We aimed to develop this and compare with existing HF risk scores. METHODS AND RESULTS: Participants in the third wave (2006-08) of the population-based Trøndelag Health Study 3 (HUNT3) were included if they reported no previous HF. Any hospital diagnoses captured during follow-up (until the end of 2018) of HF, cardiomyopathy, or hypertensive heart disease were assessed by an experienced cardiologist. Valid HF events were defined as symptoms/signs of HF and objective evidence of structural/functional abnormality of the heart at rest. The model was compared with slightly modified HF risk scores (the Health Aging and Body Composition HF risk score, the Framingham HF risk score, the Pooled Cohort equations to Prevent HF risk score, and NORRISK 2). Among 36 511 participants (mean ± SD age of 57.9 ± 13.3 years, 55.4% female), with a mean follow-up of 10.2 ± 1.3 years, 1366 developed HF (incidence rate of 3.66 per 1000 participant years). Out of the 38 relevant clinical variables assessed, we identified 12 (atrial fibrillation being the strongest) that independently predicted an HF event. The final model demonstrated good discrimination (C statistics = 0.904) and calibration, was stable in internal validation, and performed well compared with existing risk scores. The model identified that, at enrolment, 31 391 (86%), 2386 (7%), 1246 (3%), and 1488 (4%) had low, low-intermediate, high-intermediate, and high 10-year HF risk, respectively. CONCLUSIONS: Twelve clinical variables independently predicted 10-year HF risk. The model may serve well as the foundation of a practical, online risk score for HF in general practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648852.

Body Mass Index Measured Repeatedly over 42 Years as a Risk Factor for Ischemic Stroke: The HUNT Study.

BACKGROUND: Higher BMI in middle age is associated with ischemic stroke, but little is known about BMI over adulthood, and the risk for ischemic stroke as most studies relied on a single measurement of BMI. METHODS: BMI was measured four times over a period of 42 years. We calculated average BMI values and group-based trajectory models and related these to the prospective risk of ischemic stroke after the last examination in Cox models with a follow-up time of 12 years. RESULTS: A total of 14,139 participants, with a mean age of 65.2 years and 55.4% women, had information on BMI from all four examinations, and we observed 856 ischemic strokes. People with overweight and obesity over adulthood had a higher risk for ischemic stroke with a multivariable-adjusted hazard ratio of 1.29 (95% CI 1.11-1.48) and 1.27 (95% CI 0.96-1.67), respectively, when compared to normal weight participants. Excess weight tended to have stronger effects earlier than later in life. A trajectory of developing obesity throughout life was associated with higher risk than other trajectories. CONCLUSIONS: High average BMI, especially at an early age, is a risk factor for ischemic stroke. Early weight control and long-term weight reduction for those with high BMI may decrease the later occurrence of ischemic stroke.

Obesity and Risk for First Ischemic Stroke Depends on Metabolic Syndrome: The HUNT Study.

Background and Purpose: Obesity is one of the most prevalent modifiable risk factors of ischemic stroke. However, it is still unclear whether obesity itself or the metabolic abnormalities due to obesity increase the risk of ischemic stroke. We therefore investigated the association between metabolic health, weight, and risk of ischemic stroke in a large prospective cohort study. Methods: In the Norwegian HUNT study (Trøndelag Health Study), we included 35 105 participants with complete information on metabolic risk factors and relevant covariates. Metabolically unhealthy state was defined as sex specific increased waist circumference in addition to 2 or more of the following criteria: hypertension, increased blood pressure, decreased high-density lipoprotein, triglycerides or glucose, or self-reported diagnosis of diabetes. We then applied Cox proportional hazard models to estimate the risk for ischemic stroke among overweight and obese metabolically healthy and unhealthy participants compared with metabolically healthy, normal weight participants. Results: A total of 1161 ischemic stroke cases occurred after an average observation time of 11.9 years. In general, metabolically unhealthy participants were at increased risk of ischemic stroke (for obese participants: hazard ratio, 1.30 [95% CI, 1.09­1.56] compared with metabolically healthy participants with a normal body mass index). Hypertension appeared to be the most important metabolic risk factor. Metabolically healthy participants with overweight or obesity were at similar risk of ischemic stroke compared with normal weight participants (hazard ratio, 1.02 [95% CI, 0.81­1.28] for participants with obesity). Obesity and overweight even over an extended period of time seems to be benign about ischemic stroke, as long as it was not associated with metabolic abnormalities. Conclusions: Obesity was not an independent ischemic stroke risk factor in this cohort, and the risk depended more on the metabolic consequences of obesity.

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.

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.

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.

Risk of acute myocardial infarction: dyslipidemia more detrimental for men than women.

BACKGROUND: Endogenous estrogens prevent lipid peroxidation, which is pivotal in atherogenesis. Dyslipidemia may therefore be more dangerous for men than for women as a risk factor for acute myocardial infarction (AMI). A differential effect by sex has not been empirically established. METHODS: In a prospective population-based cohort study of 23,525 women and 20,725 men younger than 60 years of age at baseline, we followed participants for 12 years for a first AMI. By calculating the proportion of AMI among men with dyslipidemia attributable to the synergism between male sex and dyslipidemia, we assessed the degree to which dyslipidemia is more detrimental for men than for women. RESULTS: Dyslipidemia and male sex enhanced the effect of one another in relation to AMI risk. The proportion of AMI cases among men with dyslipidemia attributable to this synergism alone was 0.46 (95% confidence interval = 0.35 to 0.57) for high total serum cholesterol, 0.23 (0.05 to 0.41) for low high-density lipoprotein (HDL) cholesterol, and 0.52 (0.42 to 0.62) for high non-HDL cholesterol. In contrast, obesity and hypertension were equally detrimental for men and women in relation to AMI risk, with a corresponding attributable proportion of 0.02 (-0.21 to 0.25) and -0.01 (-0.27 to 0.24), respectively. CONCLUSIONS: Current clinical guidelines of dyslipidemia management do not distinguish between men and women in relation to primary prevention of AMI. Our results suggest that in middle age, dyslipidemia is much more detrimental for men than for women, and that preventing dyslipidemia has a greater potential to reduce the occurrence of AMI among men.

Age and gender differences of endothelial function in 4739 healthy adults: the HUNT3 Fitness Study.

AIMS: Endothelial dysfunction is an important marker for prognosis in patients with coronary heart disease. However, there are no reference values for endothelial function in a healthy population. Our aim was to determine the distribution of flow-mediated dilation (FMD) values by gender and age in healthy adults. METHODS: FMD was measured by ultrasound during reactive hyperaemia in the brachial artery of 4739 adults aged 20-89 years, who were free from self-reported cardiovascular or pulmonary disease. Differences in FMD across age and gender were analysed by multiple linear regression. RESULTS: Total mean ± SD FMD was 4.8 ± 4.2%, with corresponding estimates of 4.3 ± 3.9% for men and 5.3 ± 4.5% for women (p < 0.001). In total, 17% had FMD ≤0%, indicating endothelial dysfunction. FMD decreased with increasing age in both genders up to 70 years for men and 80 for women (p < 0.001). In women, age-related decline in FMD was steepest after age 45; in men, a steady decline after age 30. In men 80 years and older, FMD was higher than in men aged 50-79 years. CONCLUSIONS: The distribution of FMD in this study is representative of the respective age and gender groups of a healthy population and may be a useful reference for future studies. The high proportion of endothelial dysfunction came as a surprise. Its age and gender distribution suggest that FMD ≤0% precedes cardiovascular disease and that it may be a powerful non-invasive biomarker for identifying high-risk individuals.

Informativeness of indices of blood pressure, obesity and serum lipids in relation to ischaemic heart disease mortality: the HUNT-II study.

The informativeness of blood pressure, obesity and serum lipids associated with cardiovascular events may depend on how the indices are expressed, and mid blood pressure, waist-to-hip ratio adjusted for body-mass index (BMI) and the ratio of total to HDL cholesterol may be more informative than other expressions. Our aim was to study the informativeness of indices of blood pressure, obesity and serum lipids associated with ischaemic heart disease mortality in a large, homogeneous population. Blood pressure, weight, height, waist and hip circumference, total and HDL cholesterol, and triglycerides were measured at baseline (1995-1997) in 28,158 men and 32,573 women. Information on deaths from ischaemic heart disease (IHD) was obtained from the Causes of Death Registry in Norway from baseline until the end of 2007. Informativeness was analysed using the difference in twice the log-likelihood of a Cox model with and without each index. During 11 years of follow-up, 597 men and 418 women had died from IHD. Systolic blood pressure in men and pulse pressure in women were the most informative predictors of blood pressure, and waist-to-hip ratio adjusted for BMI was the most informative expression of obesity in both men and women. Among serum lipids, the most informative predictor was the ratio of total cholesterol to HDL cholesterol. Using more informative expressions of conventional risk factors for ischemic heart disease may improve both the validity and precision of estimates of risk, and may be useful both clinically and for preventive purposes.

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.

Mortality from ischaemic heart disease: age-specific effects of blood pressure stratified by body-mass index: the HUNT cohort study in Norway.

BACKGROUND: Blood pressure is positively associated with ischaemic heart disease (IHD) mortality, but the strength of the association declines with age, and may differ between lean and obese people. OBJECTIVE: To study the association of blood pressure with IHD mortality stratified by attained age (<65 and ≥65 years) and by body mass index (BMI). DESIGN: Prospective cohort study. SETTING: General population with baseline measurements in 1984-1986. Participants 34,633 men and 36,749 women. MEASUREMENTS, Standardised measurements of blood pressure and BMI conducted by trained personnel, and information on potentially confounding factors was retrieved from self-administered questionnaires. Information on deaths from IHD was obtained from the Causes of Death Registry in Norway from baseline until the end of 2004. RESULTS: During 2 years of follow-up, 2,529 men and 1,719 women had died from IHD. The association of blood pressure with IHD mortality was stronger in people younger than 65 years than in older age groups (p for interaction, 0.001), and the association was further modified by BMI (p for interaction, 0.001). In this age group, the RR of death from IHD associated with systolic pressure ≥160 mm Hg in lean (BMI<25) people was 5.8 (95% CI 3.8 to 8.7) compared with the reference (systolic pressure 120-139 mm Hg and BMI <25), and in overweight (BMI 25-29) and obese (BMI≥30) people, the corresponding relative risks were 2.4 (95% CI 1.6 to 3.5) and 1.6 (95% CI 0.9 to 2.8), respectively. CONCLUSION: The association of blood pressure with IHD mortality is modified by age and body mass index.