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Background: We investigated the temporal causal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) progression with the risk of dysglycemia, insulin resistance, and dyslipidemia. Methods: We included 3862, 17.7-year-old, participants from the Avon Longitudinal Study of Parents and Children, followed up for 7 years. cfPWV, cIMT, and fasting plasma samples were repeatedly measured. We computed homeostatic model assessment (HOMA) of insulin resistance and percent pancreatic beta-cell function. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models. Results: A higher cfPWV at 17.7 years was associated with higher insulin at age 24.5 years (odds ratio, 1.25 [CI, 1.08–1.44]; P =0.003), which slightly attenuated after covariates adjustment. Higher cIMT at 17.7 years was associated with lower insulin (odds ratio, 0.06 [0.01–0.95]; P =0.046) at 24.5 years, after covariate adjustments. In mixed-effect models, the 7-year progression in cfPWV (predictor) was directly associated with the increase in triglyceride (outcome). cIMT progression was associated with the 7-year increase in LDL (low-density lipoprotein), triglyceride, and glucose. In cross-lagged models, higher cfPWV at 17.7 years was associated with higher insulin ( β =0.06, SE, 0.12, P =0.014), HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years. However, insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 17.7 years were not associated with cfPWV at 24.5 years. Higher cIMT at 17.7 years was associated with reduced insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years, but not vice versa. Higher glucose at 17.7 years was associated with higher cfPWV and cIMT at 24.5 years only. Conclusions: Arterial stiffness in adolescence may be a causal risk factor for hyperinsulinemia and insulin resistance in young adulthood.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Supplemental digital content is available in the text., Purpose This study aimed to determine whether estimated cardiorespiratory fitness (CRF), fat mass (FM), lean mass (LM), and adiponectin bidirectionally associate with arterial function and structure and if CRF mediates the relationship between cardiometabolic health and arterial outcomes in 9- to 11-yr-old children drawn from the Avon Longitudinal Study of Parents and Children birth cohort, United Kingdom. Methods Brachial artery flow-mediated dilation (FMD), distensibility coefficient (DC), and carotid–radial pulse wave velocity (PWV) were measured by ultrasonography; CRF was measured during the submaximal ergometer test; total FM, trunk FM, and LM were measured by dual-energy x-ray absorptiometry; plasma adiponectin was measured by enzyme assay; and cardiometabolic health was computed based on the International Diabetes Federation criteria for diagnosing metabolic syndrome. We tested bidirectionality by including CRF, FM, LM, and adiponectin as exposures and FMD, DC, and PWV as outcomes, alternatively. Results Among 5566 participants (2816 (51%) girls; median age, 9.75 yr), CRF per body mass0.21 was directly related to DC (β (95% confidence interval) = 0.004 (

Introduction: Elevated resting heart rate in adults is an established risk factor in the lifelong process of atherogenesis and its intermediate process such as arterial stiffness. Arterial stiffness is an independent predictor of cardiovascular events. However, it is unclear whether resting heart rate temporally and bi-directionally associates with arterial stiffness especially among healthy adolescents and young adults. Hence, plausible biologic pathways through which elevated resting heart rate associate with arterial stiffness in the young population remains unknown. Hypothesis: To examine the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, with resting heart rate among adolescents aged 17.7 years. Methods: We studied 3862 (55.5% female) British adolescents followed up for 7 years until 24.5 years of age, using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England, UK. At baseline and follow-up, fat mass and lean mass were measured by dual-energy Xray absorptiometry, systolic blood pressure and heart rate by Omron BP/pulse monitor, and cfPWV by Vicorder ultrasound scan. We conducted logistic regression and cross-lagged autoregressive structural equation model analyses and adjusted for age at baseline, sex, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, time in years between measurement at 17.7 and 24.5 years, systolic blood pressure, fat mass, lean mass, and fasting plasma samples viz. low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, glucose, and insulin. Results: Participants' mean (SD) age in years was 17.72 (0.33) and 24.54 (0.73) at baseline and follow-up, respectively. Among 3862 adolescents, 10% were at moderate to high risk of elevated resting heart rate at 24.5 years. Higher cfPWV at 17.7 years was associated with the risk of elevated resting heart rate at follow-up [ Odds ratio = 1.32 (95% confidence interval 1.06 - 1.65); p=0.014]. In the cross-lagged temporal analysis, higher cfPWV at 17.7 years was associated with higher resting heart rate [ Standardized regression coefficient (β) = 0.06 standard error (SE) = 3.85, p Conclusion: We observed, for the first time, in a large healthy cohort of adolescents that arterial stiffness temporally preceded elevated resting heart rate in young adulthood, after controlling for cardiometabolic and lifestyle factors. This evidence informs that public health and clinical effort may be targeted at early detection and prevention of arterial stiffness from adolescence.

Introduction: Elevated resting heart rate in adults is an established risk factor in the lifelong process of atherogenesis and its intermediate process such as arterial stiffness. Arterial stiffness is an independent predictor of cardiovascular events. However, it is unclear whether resting heart rate temporally and bi-directionally associates with arterial stiffness especially among healthy adolescents and young adults. Hence, plausible biologic pathways through which elevated resting heart rate associate with arterial stiffness in the young population remains unknown. Hypothesis: To examine the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, with resting heart rate among adolescents aged 17.7 years. Methods: We studied 3862 (55.5% female) British adolescents followed up for 7 years until 24.5 years of age, using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England, UK. At baseline and follow-up, fat mass and lean mass were measured by dual-energy Xray absorptiometry, systolic blood pressure and heart rate by Omron BP/pulse monitor, and cfPWV by Vicorder ultrasound scan. We conducted logistic regression and cross-lagged autoregressive structural equation model analyses and adjusted for age at baseline, sex, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, time in years between measurement at 17.7 and 24.5 years, systolic blood pressure, fat mass, lean mass, and fasting plasma samples viz. low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, glucose, and insulin. Results: Participants' mean (SD) age in years was 17.72 (0.33) and 24.54 (0.73) at baseline and follow-up, respectively. Among 3862 adolescents, 10% were at moderate to high risk of elevated resting heart rate at 24.5 years. Higher cfPWV at 17.7 years was associated with the risk of elevated resting heart rate at follow-up [ Odds ratio = 1.32 (95% confidence interval 1.06 - 1.65); p=0.014]. In the cross-lagged temporal analysis, higher cfPWV at 17.7 years was associated with higher resting heart rate [ Standardized regression coefficient (β) = 0.06 standard error (SE) = 3.85, p Conclusion: We observed, for the first time, in a large healthy cohort of adolescents that arterial stiffness temporally preceded elevated resting heart rate in young adulthood, after controlling for cardiometabolic and lifestyle factors. This evidence informs that public health and clinical effort may be targeted at early detection and prevention of arterial stiffness from adolescence.

Introduction: An American Heart Association’s statement recommended investigating the natural history of arterial stiffness and blood pressure (BP) vis-à-vis the rate at which arterial stiffness and BP increase with age. Hypothesis: To test whether carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) progression independently predict increased fat mass and BP. Methods: We studied 3862 participants from the Avon Longitudinal Study of Parents and Children birth cohort. cfPWV and cIMT were measured by ultrasound scan, total and trunk fat mass, and lean mass by dual-energy Xray absorptiometry scan, body mass index (BMI), BP, heart rate, fasting insulin, glucose, high sensitivity C-reactive protein, and lipid profile were measured at ages 17.7 and 24.5 years. Participants at >75th percentile of total and trunk fat mass or having >24.9 kg/m 2 BMI were classified as overweight and obese, >75th percentile as high lean mass, and >120/80 mm Hg as elevated BP and hypertension. Data were analysed with logistic regression and linear mixed models, adjusting for cardiometabolic and lifestyle factors. Results: Among 1719 [44.5%] male and 2143 [55.5%] female participants, cfPWV at 17.7 years independently predicted systolic hypertension [Odds ratio (OR) 1.19 (1.01 - 1.40); p=0.043], diastolic hypertension [OR 1.77 (1.32 - 2.38); p2 (-0.06 - -0.01); p=0.039]. cIMT progression from age 17.7 - 24.5 years was directly associated with the 7-year increase in total fat mass, trunk fat mass, lean mass, BMI, and diastolic BP. Conclusions: Arterial stiffness and cIMT progression independently predicted obesity, high lean mass, and incident hypertension among young adults.

Introduction: Carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) are strong predictors of cardiovascular and all-cause mortality in adults. However, due to the unavailability of hard outcomes among adolescents and young adults, it remains unclear how cfPWV and cIMT predict metabolic outcomes in these age groups. Hypothesis: We tested whether cfPWV and cIMT during adolescence similarly or differently predict higher insulin, glucose, plasma lipid, and increased inflammation in young adulthood. Methods: Altogether 3862 British (56% females) participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England, UK were studied. cfPWV was measured by Vicorder device, cIMT by CardioHealth ultrasound scan, systolic blood pressure (BP) and heart rate by Omron BP/pulse monitor, total fat mass and lean mass by dual-energy Xray absorptiometry, moderate to vigorous physical activity by accelerometer, and smoking status by questionnaire. Insulin, plasma glucose, lipid profiles, and high sensitivity C-reactive protein were measured during a fasting state. Insulin resistance (HOMA-IR) was estimated from (insulin x glucose)/22.5. We conducted linear regression analyses and adjusted for cardiometabolic and lifestyle factors at 17.7 years. Results: Participants' mean (SD) age in years at different time points were [17.72 (0.33) and 24.54 (0.73)]. cfPWV at age 17.7 years was inversely associated with high-density lipoprotein cholesterol [β = -0.32 (CI: -0.60 to -0.04); p=0.028] and directly associated with insulin [0.28 (0.05 to 0.50); p=0.019] and HOMA-IR [0.28 (0.04 to 0.53); p=0.026] at 24.5 years. cIMT at age 17.7 years was inversely associated with insulin [-0.33 (-0.59 to -0.07); p=0.024] and HOMA-IR [-0.32 (-0.59 to -0.04); p=0.026] at 24.5 years. cfPWV and cIMT at 17.7 years were unrelated to other metabolic and inflammatory markers at 24.5 years. Conclusions: Arterial stiffness during adolescence may be a novel risk factor for predicting reduced high-density lipoprotein cholesterol and increased insulin resistance in young adults. However, carotid wall thickening in adolescence predicted higher insulin sensitivity 7 years later.

Fatty liver disease (FLD) and hypertension are separately associated with cardiovascular (CV) mortality. While the two conditions are established as separate predictors of CV outcomes, FLD and hypertension are interrelated in multiple ways. A biological interaction in respect to CV disease outcomes could exist between FLD and hypertension. In this study, we investigated the joint effect and interaction of FLD and hypertension regarding CV mortality using an interaction framework. Using a population-based cohort, we followed 1,569 middle-aged non-diabetic Finnish men for 34 years. We computed the fatty liver index and considered values ≥60 as indicative of FLD. We defined hypertension as either i) self-reported hypertension and a confirmed use of antihypertension medication, or ii) a mean systolic ≥160 or diastolic ≥105 blood pressure on baseline examination. The choice of the blood pressure measurement threshold to define hypertension was based on a sensitivity analysis. With adjustment for age, body mass index, smoking, and alcohol consumption, separate and combined effects of FLD and hypertension and their interaction at the multiplicative and additive scales regarding all-cause and CV death were assessed using Cox proportional hazards models. Among the men, 372 had FLD and 342 had hypertension. FLD and hypertension coexisted in 134 men. FLD and hypertension associated, independently and combined, with an increased hazard of all-cause and CV deaths. Non-cardiovascular mortality associated with FLD, but not with hypertension. We found a negative interaction between FLD and hypertension regarding the hazard of all-cause (relative excess risk due to interaction [RERI], -0.97; 95% confidence interval [CI], -1.65 to -0.28) and CV mortality (RERI, -1.74; 95% CI, -2.98 to -0.50). The interaction was also found on a multiplicative scale. We found evidence of a negative interaction between FLD and hypertension in respect to CV mortality. Our findings were robust to different definitions of hypertension but were more relevant at high blood pressure thresholds. We thus recommend adjusting for FLD or hypertension when studying the effect of the other condition on mortality or CV diseases in middle-aged men and call for further research on the topic.

Introduction: Evidence on the associations of fat mass and lean mass with changes in carotid-femoral pulse wave velocity (cfPWV) and carotid intima-media thickness (cIMT), markers of pre-clinical atherosclerosis, from adolescence through young adulthood is lacking. Previous studies have reported strong associations of body mass index (BMI), a measure of adiposity, with these markers. However, it is unclear if increased BMI in relation to these markers represents a pathological process or physiological adaptation. A knowledge gap also exists on the independent associations of blood pressure (BP) measured from childhood through young adulthood with changes in cfPWV and cIMT between ages 17 and 24.5 years. Hypothesis: We assessed the hypothesis whether lean mass and systolic BP, independent of fat mass, cardiometabolic and lifestyle factors, measured at age 9, 17, and 24.5 years drive a 7-year change in cfPWV and cIMT. Methods: We studied 3863 British children from the Avon Longitudinal Study of Parents and Children's birth cohort (56% females). fat mass and lean mass were measured by dual-energy Xray absorptiometry, systolic and diastolic BP by Omron BP/pulse monitor, cfPWV by Vicorder device, and cIMT by CardioHealth ultrasound scan. All exposures were categorized in tertiles of low, normal, and high, with the low category as the reference group. We conducted linear mixed effect model analyses and adjusted for age, sex, low-density lipoprotein, C-reactive protein, fasting blood glucose, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, time in years between measure at 9 and 24.5 years, and systolic BP, fat mass, and/or lean mass depending on the predictor. Results: Participants mean (SD) age in years at different time points were [9.83 (0.30); 17.72 (0.33); 24.54 (0.73)]. Over a 15-year follow-up period, persistent exposure to high lean mass effect estimate =0.006 (CI 0.001 - 0.010, p=0.022), high systolic BP 0.013 (0.009 - 0.017, p Conclusion: For the first time, we showed in a healthy cohort that persistent exposure to higher lean mass and BP from childhood independently drives arterial wall adaptation in early adulthood. These arterial changes are likely normal responses to growth and maturation rather than subclinical signs of arterial diseases. Thus, cumulative exposure to high BMI in relation to higher cfPWV and cIMT may not indicate a deleterious effect of adiposity.

Background: Animal and plant protein intakes have indicated opposite associations with cardiovascular mortality risk. Whether dietary proteins are associated with risk of heart failure (HF) is unclear. Thus, we examined the associations of proteins from different food sources with risk of HF. Methods and Results: The study included 2441 men aged 42 to 60 years at the baseline examinations in 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Protein intakes at baseline were assessed with 4-day dietary records. Data on incident HF cases were obtained from national registers. HF risk according to protein intake was estimated by Cox proportional hazard ratios. During the mean follow-up of 22.2 years, 334 incident HF cases occurred. Higher intake of total protein indicated a trend toward increased risk of HF (multivariable-adjusted hazard ratio in the highest versus lowest quartile=1.33; 95% confidence interval: 0.95–1.85; P -trend=0.05). The associations between specific types and sources of protein with incident HF were consistent with this overall finding although not all associations reached statistical significance. For example, the hazard ratio in the highest versus lowest quartile was 1.43 (95% confidence interval: 1.00–2.03; P -trend=0.07) for total animal protein and 1.17 (95% confidence interval: 0.72–1.91; P -trend=0.35) for total plant protein. Conclusions: In middle-aged men, higher protein intake was marginally associated with increased risk of HF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03221127

Arterial wall remodeling is a central multifactorial process in the development and progression of cardiovascular diseases. We employed an approach aimed at observing genetic variants associated with the progression of carotid intima-media thickness (cIMT) in order to identify novel pathways effecting vessel remodeling. This was achieved by conducting gene-centric analysis of 400,000 variants in 3,042 subjects with repeated cIMT measurements. Rs16997464 on chr22 intergenic between neutrophil cytosolic factor-4 ( NCF4) and colony stimulating factor 2 receptor beta ( CSF2RB ) was associated with cIMT progression at array-wide significance (p -7 ). The potential causative genes within this locus were investigated using a human vascular and non-vascular tissue biobank. Expression of 9 genes near rs16997464, were analyzed with the most significant association being with NCF4 in aortic adventitia. The effect of the variant on the function of the NCF4 gene product was further analyzed by comparing the oxidative burst capacity of neutrophils from subjects with different rs16997464 genotypes. We observed that neutrophils homozygous for the minor T allele, associated with slower cIMT progression, produced more extracellular ROS than neutrophils homozygous for the G allele, indicating a functional effect of rs16997464 on the NCF4 gene product p40 phox , a component of the NADPH oxidase 2 complex (NOX2). In parallel, we investigated if the chr22 locus also influenced the cellular composition of the atherosclerotic plaque, by utilizing data from the Athero-Express Biobank. Here we found that the minor T allele associated with a higher smooth muscle cell (SMC) content in the plaque. Finally, using a partial ligation model in mice where ncf4 is mutated, resulting in a reduced but not absent NOX2-associated ROS formation, we observed a reduced neointima formation in the ncf4 -mutated strain compared with wild-type littermates. Thus, this study identified rs16997464 in the NCF4-CSF2RB locus as a novel genetic determinant of cIMT progression, and provides evidence suggesting that NCF4 is involved in SMC proliferation and alteration of vessel wall pathophysiology.

Introduction: Most of the recent dairy studies, including multiple meta-analyses, show either no relationship or an inverse association between total dairy intake and risk of cardiovascular diseases. Some of these studies have suggested that especially fermented rather than non-fermented dairy might provide benefits on cardiovascular health, but the data is inconclusive. Also, the average dairy intake has been modest in many study populations, which reduces the generalizability of the findings to populations with high dairy intake. Hypothesis: We assessed the hypothesis that fermented and non-fermented dairy products have distinct associations with the risk of coronary heart disease (CHD) in men from eastern Finland, a population with high intake of dairy products. Methods: A total of 1981 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study from eastern Finland, aged 42-60 years, with no CHD at baseline, were included. The consumption of foods was assessed with instructed 4-day food recording by household measures. Dairy products with fat content Results: The mean±SD intakes were 733±375 g/d for total, 187±218 g/d for fermented and 546±345 g/d for non-fermented dairy. Low-fat products comprised 87% (162±218 g/d) of the fermented and 43% (317±291 g/d) of the non-fermented dairy intake. During the mean follow-up of 20.1 years, 472 CHD events occurred. The multivariable-adjusted hazard ratio (95% CI) in the highest (>280 g) vs. the lowest (727 g) vs. the lowest ( Conclusions: Our results suggest that low-fat fermented dairy products are associated with a lower risk of CHD, whereas low-fat non-fermented dairy products are associated with a higher risk in a population with high intake of dairy products.

Introduction: The epidemiological evidence of the role of dietary saturated fatty acids (SFA) in the etiology of coronary heart disease (CHD) is inconsistent. However, the proportions of different SFAs in different foods vary, and food sources of SFA (such as dairy and meat products) have had distinct associations with risk of CHD and its risk factors. Hypothesis: We assessed the hypothesis that SFA from different food sources have distinct associations with CHD risk in men. Methods: A total of 1981 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study from eastern Finland, aged 42-60 years and free of CHD at baseline, were included. The consumption of foods was assessed with instructed 4-day food recording by household measures. Dietary intakes were adjusted for total energy using the residuals method. Multivariable-adjusted Cox regression analyses included age, examination year, body mass index, diabetes, hypertension, family history of CHD, smoking, education, leisure-time physical activity, and intakes of alcohol, energy, fiber, polyunsaturated fatty acids, and fruits, berries and vegetables. Fatal and nonfatal CHD events were ascertained from national registries, with no loss to follow-up. Results: The mean±SD total SFA intake was 49.1±10.4 g/d (18.1 E%). SFA from dairy (16.1±7.7 g/d, excluding butter), butter (16.0±11.1 g/d), plant sources (6.7±5.0 g/d), processed red meat (4.7±4.2 g/d), and unprocessed red meat (3.6±2.7 g/d) contributed most to the total intake. During the mean follow-up of 19.6 years, 458 CHD events occurred. The extreme-quartile hazard ratios (95% CIs) were 1.08 (0.79-1.47, P-trend=0.57) for the highest vs. the lowest quartile of total SFA, 0.99 (0.75-1.32, P-trend=0.93) for total dairy SFA, 1.17 (0.84-1.63, P-trend=0.45) for butter SFA, 0.96 (95% CI 0.70-1.32, P-trend=0.62) for plant SFA, 1.09 (0.82-1.44, P-trend=0.76) for processed red meat SFA, and 1.15 (0.88-1.49, P-trend=0.29) for SFA from unprocessed red meat. Only SFA from fermented dairy (mean±SD intake 4.6±4.6 g/d) was associated with the risk (hazard ratio in the highest vs. the lowest quartile 0.69, 95% CI 0.52-0.91, P-trend=0.02). The associations were not appreciably different with a shorter, 10-y follow-up (199 cases). Conclusions: Our results suggest an overall non-significant role for SFA intake in the CHD risk and little difference in the associations with SFA from various food sources. Because milk is the raw material in all dairy products, the inverse association with fermented dairy likely reflects other constituents in these products than SFA.

Introduction: Different protein sources, such as processed red meat and fish have indicated distinct associations with risk of heart failure. Whether these distinct associations are partly due to the differences in proteins themselves remains unclear. Thus, we examined the associations of proteins from different food sources with risk of heart failure in Finnish male subjects. Hypothesis: We hypothesized that proteins from different dietary sources would have distinct associations with heart failure risk. Methods: The study included 2441 men aged 42-60 y at the baseline examinations in 1984-1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Protein intakes at baseline were assessed with 4-d dietary records. Data on incident heart failure cases were obtained from national registers. The multivariable-adjusted risk of heart failure according to protein intake was estimated by Cox proportional hazard ratios. Multivariable analyses included age, examination year, education, income, family history of ischaemic heart disease, smoking, leisure-time physical activity, and intakes of alcohol, energy, fiber, and saturated, monounsaturated, polyunsaturated and trans fatty acids. Results: During the mean follow-up time of 22.2 y, 334 incident cases of heart failure occurred. Total protein (multivariable-adjusted extreme-quartile HR 1.45, 95% CI: 1.04-2.00, P-trend 0.01), animal protein (HR 1.56, 95% CI: 1.12-2.17, P-trend 0.01) and dairy protein (HR 1.53, 95% CI: 1.11-2.11, P-trend 0.01) intakes were associated with increased risk of heart failure. Especially protein from fermented dairy products associated with higher risk (HR 1.48, 95% CI: 1.08-2.02, P-trend 0.002). Adjustment for the potential effect mediators [body mass index and diseases or medications (coronary heart disease, hypertension, type 2 diabetes, lipid-lowering or heart medications) at baseline and during the follow-up] slightly attenuated the associations, but associations of animal, dairy and fermented dairy protein remained statistically significant. Plant protein intake had no association with heart failure risk (HR 1.00, 95% CI: 0.63-1.59, P-trend 0.82). Conclusions: Our data suggest that high intake of protein, especially from animal and dairy sources, may increase the risk of heart failure.

Background— Atrial fibrillation (AF) is a common cardiac arrhythmia. Regular fish consumption has been shown to reduce the risk of AF in some but not all studies. Long-chain n-3 polyunsaturated fatty acids (PUFAs) from fish have been suggested to account for these beneficial effects. We tested this hypothesis by studying the association between the serum long-chain n-3 PUFAs eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid and risk of AF in men. Methods and Results— A total of 2174 men from the prospective population-based Kuopio Ischemic Heart Disease Risk Factor Study, 42 to 60 years old and free of AF at baseline in 1984 to 1989, were studied. During the average follow-up time of 17.7 years, 240 AF events occurred. In the Cox proportional hazards model, the multivariable-adjusted hazard ratio in the highest (>5.33%) versus the lowest (P for trend=0.07). Evaluated individually, only serum docosahexaenoic acid was associated with the risk of AF (hazard ratio in the highest versus the lowest quartile 0.62, 95% confidence interval 0.42 to 0.92, P for trend=0.02). Exclusion of subjects (n=233) with myocardial infarction or congestive heart failure either at baseline or that preceded the AF event during follow-up slightly strengthened the associations. Serum intermediate chain-length n-3 PUFA, α-linolenic acid, or hair methylmercury concentration were not associated with the risk. Conclusions— An increased concentration of long-chain n-3 PUFAs in serum, a marker of fish or fish oil consumption, may protect against AF. Serum docosahexaenoic acid concentration had the greatest impact.

Objective— High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD. Methods and Results— Altogether, 148 members of Finnish low-HDL families and 133 healthy control subjects participated in our study. HDL particle size was significantly smaller in affected family members (HDL ≤10th Finnish age-sex specific percentile) compared with unaffected family members and control subjects (9.1±0.04 nm versus 9.5±0.05 nm, P P 2b particles as well as preβ-HDL concentration were significantly decreased among the affected family members. Mean IMT was significantly higher in the affected family members than in the control subjects (0.85±0.01 mm versus 0.79±0.01 mm; P 2b , systolic blood pressure, and preβ-HDL were significant independent determinants of mean IMT. Conclusions— The decreased levels of HDL 2b and preβ-HDL reflect the potentially efflux-deficient HDL subspecies profile in the affected low-HDL family members. Decreased HDL particle size caused by the decrease of plasma concentration of HDL 2b and decreased preβ-HDL levels correlate with increased IMT.

Objective— Mercury has been suggested to have negative effects on cardiovascular health. We investigated the effects of high mercury content in hair on the risk of acute coronary events and cardiovascular and all-cause mortality in men from eastern Finland. Methods and Results— The population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort of 1871 Finnish men aged 42 to 60 years and free of previous coronary heart disease (CHD) or stroke at baseline was used. During an average follow-up time of 13.9 years, 282 acute coronary events and 132 cardiovascular disease (CVD), 91 CHD, and 525 all-cause deaths occurred. Men in the highest third of hair mercury content (>2.03 μg/g) had an adjusted 1.60-fold (95% CI, 1.24 to 2.06) risk of acute coronary event, 1.68-fold (95% CI, 1.15 to 2.44) risk of CVD, 1.56-fold (95% CI, 0.99 to 2.46) risk of CHD, and 1.38-fold (95% CI, 1.15 to 1.66) risk of any death compared with men in the lower two thirds. High mercury content in hair also attenuated the protective effects of high-serum docosahexaenoic acid plus docosapentaenoic acid concentration. Conclusions— High content of mercury in hair may be a risk factor for acute coronary events and CVD, CHD, and all-cause mortality in middle-aged eastern Finnish men. Mercury may also attenuate the protective effects of fish on cardiovascular health.

Development of hypertension has been linked to chronic low-grade inflammation. However, it is not known whether this connection is mediated by features of the metabolic syndrome or smoking, or their changes, which themselves have been linked to inflammation. We studied the predictive value of highly sensitive C-reactive protein (hs-CRP), smoking, and abdominal obesity to the development of hypertension in an 11-year follow-up of a population-based study cohort comprising 379 middle-aged normotensive men. During the follow-up, 124 men (33%) developed hypertension. Men with hs-CRP ≥3.0 mg/L were 2.8× (95% confidence interval, 1.2 to 6.6) more likely to develop hypertension than with hs-CRP

Background— Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression, but the evidence from clinical trials is controversial. In the first 3 years of the ASAP trial, the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women. This article examines the 6-year effect of supplementation on common carotid artery (CCA) intima-media thickness (IMT). Methods and Results— The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol ≥5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom completed the study. Atherosclerotic progression was assessed ultrasonographically. In covariance analysis in both sexes, supplementation reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to 46, P =0.014), in men by 33% (95% CI, 4 to 62, P =0.024) and in women by 14% (not significant). In both sexes combined, the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group (25% treatment effect, 95% CI, 2 to 49, P =0.034). In men, this treatment effect was 37% (95 CI, 4 to 69, P =0.028). The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on HDL cholesterol. Conclusions— These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C slows down atherosclerotic progression in hypercholesterolemic persons.

Background —Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated ( HFE ) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results —Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1.1 to 4.8; P =0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions —Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.

Background Epidemiological studies and animal experiments have provided evidence supporting the role of lipid peroxidation in atherogenesis and cardiovascular diseases. Direct evidence linking lipid oxidation to atherosclerotic progression in humans, however, has been lacking. We investigated the association of lipid oxidation products with the progression of early carotid atherosclerosis in hypercholesterolemic men from eastern Finland. Methods and Results Twenty subjects with a fast progression and 20 with no progression of carotid atherosclerosis in 3 years were selected from >400 participants in the Kuopio Atherosclerosis Prevention Study. Progression of carotid atherosclerosis was assessed by high-resolution B-mode ultrasonography. Serum 7β-hydroxycholesterol, a major oxidation product of cholesterol in membranes and lipoproteins, and seven other cholesterol oxidation products were measured by isotope dilution–mass spectrometry, lipid hydroperoxides in LDL fluorometrically as thiobarbituric acid–reactive substances (TBARS) and oxidation susceptibility of LDL and VLDL kinetically. High concentrations of serum 7β-hydroxycholesterol (β=.47, P =.0005), cigarette smoking (β=.35, P =.0167), and LDL TBARS (β=.23, P =.0862) and an increased oxidation susceptibility of VLDL+LDL (β=.22, P =.1114) were the strongest predictors of a 3-year increase in carotid wall thickness of more than 30 variables tested in step-up least-squares regression models. A 10-variable model explained 60% of the atherosclerotic progression. In a multivariate logistic model, the risk of experiencing a fast progression increased by 80% ( P =.013) per unit (μg/L) of 7β-hydroxycholesterol. Conclusions The findings of this study provide further evidence to support an association between lipid oxidation and atherogenesis in humans.

Background: Fish consumption has been associated with reduced risk of sudden cardiac death. It has been suggested that the long-chain omega-3 fatty acids from fish are responsible for the beneficial effects of fish consumption. The QT interval on the ECG measures the duration of ventricular repolarization, and a long QT interval is one of the major risk factors for sudden cardiac death. Our goal was to study the association between the serum long-chain omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) and QT interval duration in middle aged men. As fish is also the major source of methylmercury, an environmental contaminant proposed to have adverse cardiovascular effects, we also evaluated the impact of methylmercury exposure on the QT duration. Methods: A total of 1411 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42–60 years and free of cardiovascular disease, were included. A standardized resting 12-lead ECG was used for recording. Men with QRS ≥120 ms were excluded. The heart rate-corrected QT interval (QTc) was calculated using the Bazett’s formula. Prolonged QTc was defined as QTc >440 ms. Quartiles of the percentage of EPA, DPA and DHA of all serum fatty acids were used as the exposure. Hair mercury in quartiles was used as a marker for methylmercury exposure. Results: The mean±SD concentrations were 4.70±1.61% for EPA+DPA+DHA, 1.69±0.92% for EPA, 0.55±0.10% for DPA and 2.46±0.74% for DHA, of all serum fatty acids. The mean QTc interval in the quartiles of serum EPA+DPA+DHA was 417, 417, 415 and 414 ms (P for trend 0.02), after adjustment for age, examination year, smoking, alcohol intake, physical activity, body mass index, education, income, diabetes, treated hypertension and arrhythmia medication. Prolonged QTc was found in 169 of the 1411 men (12%). The multivariate-adjusted odds ratio (OR) for prolonged QTc in the quartiles of EPA+DPA+DHA was 1, 0.90, 0.83 and 0.63 [95% confidence interval (CI) 0.39–1.02, P for trend 0.05]. The OR in the highest vs. the lowest quartile was 0.58 (95% CI 0.36–0.93, P for trend 0.03) for EPA, 0.68 (95% CI 0.43–1.09, P for trend 0.06) for DPA and 0.59 (95% CI 0.35–0.98, P for trend 0.04) for DHA. The mean±SD hair mercury concentration was 1.9±2.0 μg/g. Hair mercury was not associated with QTc, unadjusted or adjusted. The multivariate-adjusted OR for prolonged QTc in the quartiles of hair mercury was 1, 0.97, 0.99 and 1.04 (95% CI 0.64–1.69), P for trend 0.80. Conclusions: Increased concentration of long-chain omega-3 fatty acids in serum, a marker of fish or fish oil consumption, appears to protect against prolonged QTc in eastern Finnish middle-aged men. Methylmercury exposure is not associated with QTc in this study population.