Publications by authors named "Jukka Salonen"

139 Publications

A healthy Nordic diet score and risk of incident CHD among men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Br J Nutr 2021 Apr 7:1-8. Epub 2021 Apr 7.

University of Eastern Finland, Institute of Public Health and Clinical Nutrition, P.O. Box 1627, 70211 Kuopio, Finland.

Healthy Nordic diet has been beneficially associated with CHD risk factors, but few studies have investigated risk of developing CHD. We investigated the associations of healthy Nordic diet with major CHD risk factors, carotid atherosclerosis and incident CHD in middle-aged and older men from eastern Finland. A total of 1981 men aged 42-60 years and free of CHD at baseline in 1984-1989 were investigated. Diet was assessed with 4-d food recording and the healthy Nordic diet score was calculated based on the Baltic Sea Diet Score. Carotid atherosclerosis was assessed by ultrasonography of the common carotid artery intima-media thickness in 1053 men. ANCOVA and Cox proportional hazards regression analyses were used for analyses. Healthy Nordic diet score was associated with lower serum C-reactive protein (CRP) concentrations (multivariable-adjusted extreme-quartile difference 0·66 mg/l, 95 % CI 0·11, 1·21 mg/l) but not with serum lipid concentrations, blood pressure or carotid atherosclerosis. During the average follow-up of 21·6 years (sd 8·3 years), 407 men had a CHD event, of which 277 were fatal. The multivariable-adjusted hazard ratios in the lowest v. the highest quartile of the healthy Nordic diet score were 1·15 (95 % CI 0·87, 1·51) for any CHD event (Ptrend 0·361) and 1·44 (95 % CI 0·99, 2·08) (Ptrend 0·087) for fatal CHD event. We did not find evidence that adherence to a healthy Nordic diet would be associated with a lower risk of CHD or with carotid atherosclerosis or major CHD risk factors, except for an inverse association with serum CRP concentrations.
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http://dx.doi.org/10.1017/S0007114521001227DOI Listing
April 2021

Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts.

Sci Rep 2021 Jan 12;11(1):611. Epub 2021 Jan 12.

Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland.

High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.
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http://dx.doi.org/10.1038/s41598-020-79931-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804469PMC
January 2021

Serum copper-to-zinc-ratio and risk of incident infection in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Eur J Epidemiol 2020 Dec 13;35(12):1149-1156. Epub 2020 May 13.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.

Infections are one of the main causes of mortality in elderly due to the decrease of immune response, for which copper (Cu) and zinc (Zn) are claimed to be crucial. High serum copper-to-zinc-ratio (Cu/Zn-ratio) has been reported with infections, but little is known whether it could also predict the incidence of infections. The study cohort consisted of 1975 men aged 42-60 years and free of severe infectious disease at baseline in 1984-1989 from the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. The main outcome was an incident infection leading to hospitalization. Cox proportional hazards regression models were used for statistical analysis. During the average follow-up of 19.2 years, 636 incident first cases of infections were diagnosed. The hazard ratio (HR) of developing an incident infectious disease in the highest compared to the lowest Cu/Zn-ratio quartile after adjustment for age and baseline examination year was 1.35 [95% confidence interval (CI) = 1.07-1.69, P-trend across quartiles = 0.005]. The association was slightly attenuated after additional adjustment for potential confounders (HR = 1.21, 95% CI = 0.96-1.53, P-trend = 0.054). Furthermore, higher serum Cu concentration was associated with higher risk of an incident infection. The multivariable-adjusted HR was 1.39 (95% CI = 1.10-1.75, P-trend = 0.005) in the highest versus the lowest serum Cu quartile. Serum Zn concentration was not associated with the risk (multivariable-adjusted extreme-quartile HR = 0.83, 95% CI = 0.67-1.04, P-trend = 0.218). In conclusion, our data suggest that an increased Cu/Zn-ratio and especially serum Cu concentration are associated with increased risk of incident infections in middle-aged and older men in Eastern Finland.
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http://dx.doi.org/10.1007/s10654-020-00644-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762744PMC
December 2020

Associations of dietary choline intake with risk of incident dementia and with cognitive performance: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2019 12;110(6):1416-1423

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background: Moderate egg intake has been associated with better cognitive performance in observational studies. This association may be due to the rich content of choline, especially phosphatidylcholine, in eggs because choline has been suggested to have a role in the prevention of cognitive decline.

Objectives: We investigated the associations of dietary choline intake with the risk of incident dementia and with cognitive performance in middle-aged and older men in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study.

Methods: A population-based sample of 2497 dementia-free men aged 42-60 y was examined in 1984-1989. A subset of 482 men completed 5 different cognitive performance tests 4 y later. Dementia and Alzheimer disease diagnoses were retrieved from Finnish health registers. Dietary intakes were assessed with the use of 4-d food records at baseline. Cox regression and ANCOVA were used for the analyses. All analyses were also stratified by the apolipoprotein E phenotype (APOE-ε4 compared with other phenotypes). These data were available for 1259 men.

Results: The mean ± SD total choline intake was 431 ± 88 mg/d, of which 188 ± 63 mg/d was phosphatidylcholine. During a 21.9-y follow-up, 337 men were diagnosed with dementia. Those in the highest compared with the lowest phosphatidylcholine intake quartile had 28% (95% CI: 1%, 48%; P-trend = 0.02 across quartiles) lower multivariable-adjusted risk of incident dementia. Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning. For example, higher intakes were associated with better performance in verbal fluency and memory functions. The APOE phenotype had little or no impact on the associations.

Conclusion: Higher phosphatidylcholine intake was associated with lower risk of incident dementia and better cognitive performance in men in eastern Finland. This trial was registered at clinicaltrials.gov as NCT03221127.
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http://dx.doi.org/10.1093/ajcn/nqz148DOI Listing
December 2019

Egg consumption, cholesterol intake, and risk of incident stroke in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2019 07;110(1):169-176

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background: Epidemiologic studies suggest inverse associations between consumption of egg, a major source of dietary cholesterol, and stroke. However, the evidence of the relation remains limited, especially among carriers of apolipoprotein E4 (apoE4), which influences cholesterol metabolism.

Objective: The aim of this study was to investigate associations of egg and cholesterol intakes with risk of stroke and with the major stroke risk factor, blood pressure, in middle-aged and older men from eastern Finland and whether apoE phenotype could modify these associations.

Methods: A total of 1950 men aged 42-60 y in 1984-1989 were included at the baseline examinations of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on apoE phenotype were available for 1015 men. Dietary intakes were assessed with 4-d food records at baseline and incident stroke events were assessed by record linkage to hospital discharge registries. Cox proportional hazards regression analyses were used to estimate associations with stroke risk. Associations with baseline blood pressure were evaluated with ANCOVA.

Results: During the mean ± SD follow-up of 21.2 ± 7.2 y, there were 217 incidences of any stroke: 166 of ischemic stroke and 55 of hemorrhagic stroke. Comparing the highest egg intake quartile with the lowest, the multivariable-adjusted HRs were 0.81 for total stroke (95% CI: 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI: 0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective HRs for the highest cholesterol intake quartile compared with the lowest were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75). Diastolic blood pressure was 1.6 mm Hg (P-trend = 0.04) lower in the highest egg intake quartile compared with the lowest, but there were no associations with systolic blood pressure or with cholesterol intake. ApoE phenotype (32% had apoE4 phenotype) did not modify the associations.

Conclusion: Neither egg nor cholesterol intakes were associated with stroke risk in this cohort, regardless of apoE phenotype.This trial was registered at www.clinicaltrials.gov as NCT03221127.
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http://dx.doi.org/10.1093/ajcn/nqz066DOI Listing
July 2019

Serum long-chain omega-3 fatty acids, hair mercury and exercise-induced myocardial ischaemia in men.

Heart 2019 09 4;105(18):1395-1401. Epub 2019 May 4.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Objective: Long-chain omega-3 polyunsaturated fatty acids (PUFA) from fish have been inversely associated with coronary heart disease (CHD) risk. Fish may also contain methylmercury, which has been associated with higher CHD risk and may diminish the cardioprotective effect of long-chain omega-3 PUFA. We investigated the associations of serum long-chain omega-3 PUFA and hair mercury with the odds for myocardial ischaemia during exercise.

Methods: A total of 2199 men from the Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 years were studied in 1984-89. Of the 2199 men, 342 had history of CHD. The men performed a maximal symptom-limited exercise stress test using an electrically braked bicycle ergometer. ORs for exercise-induced myocardial ischaemia were estimated with logistic regression.

Results: In the multivariable analysis, those in the highest versus lowest serum long-chain omega-3 PUFA quartile had 33% lower odds of myocardial ischaemia (OR 0.67, 95% CI 0.51 to 0.87, p-trend=0.006). The association was stronger among those with CHD history (OR 0.10, 95% CI 0.03 to 0.39, p-trend <0.001), than among those without (OR 0.80, 95% CI 0.57 to 1.12, p-trend=0.17) (p-interaction=0.01). Higher hair mercury concentration was associated with increased odds for myocardial ischaemia in the entire population (OR 1.62, 95% CI 1.22 to 2.14, p-trend=0.002).

Conclusion: Higher circulating concentrations of the long-chain omega-3 PUFAs, a marker for fish consumption, were associated with lower occurrence of exercise-induced myocardial ischaemia, but only among men with CHD history. Hair mercury concentration was directly associated with the occurrence of exercise-induced myocardial ischaemia in the entire study population.
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http://dx.doi.org/10.1136/heartjnl-2019-314755DOI Listing
September 2019

Dietary proteins and protein sources and risk of death: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2019 05;109(5):1462-1471

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background: Previous studies investigating protein intake in relation to mortality have provided conflicting results.

Objective: We investigated the associations of dietary protein and protein sources with risk of disease death in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study.

Methods: The study population consisted of 2641 Finnish men, aged 42-60 y at baseline in 1984-1989. We estimated protein intakes with 4-d dietary records at baseline and collected data on disease deaths from the national Causes of Death Register. Cox proportional hazards regression models were used to estimate HRs and 95% CIs.

Results: During the average follow-up of 22.3 y, we observed 1225 deaths due to disease. Higher intakes of total protein and animal protein had borderline statistically significant associations with increased mortality risk: multivariable-adjusted HR (95% CI) in the highest compared with the lowest quartile for total protein intake = 1.17 (0.99, 1.39; P-trend across quartiles = 0.07) and for animal protein intake = 1.13 (0.95, 1.35; P-trend = 0.04). Higher animal-to-plant protein ratio (extreme-quartile HR = 1.23; 95% CI: 1.02, 1.49; P-trend = 0.01) and higher meat intake (extreme-quartile HR = 1.23; 95% CI: 1.04, 1.47; P-trend = 0.01) were associated with increased mortality. When evaluated based on disease history at baseline, the association of total protein with mortality appeared more evident among those with a history of type 2 diabetes, cardiovascular disease, or cancer (n = 1094) compared with those without disease history (n = 1547) (P-interaction = 0.05 or 0.07, depending on the model). Intakes of fish, eggs, dairy, or plant protein sources were not associated with mortality.

Conclusions: Higher ratio of animal to plant protein in diet and higher meat intake were associated with increased mortality risk. Higher total protein intake appeared to be associated with mortality mainly among those with a predisposing disease. This trial was registered at clinicaltrials.gov as NCT03221127.
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http://dx.doi.org/10.1093/ajcn/nqz025DOI Listing
May 2019

Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study.

Hum Mol Genet 2019 04;28(8):1381-1391

Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control.
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http://dx.doi.org/10.1093/hmg/ddz011DOI Listing
April 2019

Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis.

Am J Epidemiol 2017 Oct;186(8):899-907

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.
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http://dx.doi.org/10.1093/aje/kwx149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860526PMC
October 2017

Alcohol Consumption and Common Carotid Intima-Media Thickness: The USE-IMT Study.

Alcohol Alcohol 2017 Jul;52(4):483-486

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.

Aims: Epidemiological evidence indicates a protective effect of light to moderate alcohol consumption compared to non-drinking and heavy drinking. Although several mechanisms have been suggested, the effect of alcohol on atherosclerotic changes in vessel walls is unclear. Therefore, we explored the relationship between alcohol consumption and common carotid intima media thickness, a marker of early atherosclerosis in the general population.

Methods: Individual participant data from eight cohorts, involving 37,494 individuals from the USE-IMT collaboration were used. Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) with alcohol consumption.

Results: The mean age was 57.9 years (SD 8.6) and the mean CIMT was 0.75 mm (SD 0.177). About, 40.5% reported no alcohol consumed, and among those who drank, mean consumption was 13.3 g per day (SD 16.4). Those consuming no alcohol or a very small amount (<5 g per day) had significantly lower common CIMT values than those consuming >10 g per day, after adjusting for a range of confounding factors.

Conclusion: In this large CIMT consortium, we did not find evidence to support a protective effect of alcohol on CIMT.
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http://dx.doi.org/10.1093/alcalc/agx028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860521PMC
July 2017

HDL-C and Mortality.

Authors:
Jukka T Salonen

J Am Coll Cardiol 2017 04;69(13):1759

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http://dx.doi.org/10.1016/j.jacc.2016.11.089DOI Listing
April 2017

Clustering of cardiovascular risk factors and carotid intima-media thickness: The USE-IMT study.

PLoS One 2017 21;12(3):e0173393. Epub 2017 Mar 21.

Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation.

Methods: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group.

Results: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women.

Conclusion: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173393PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360240PMC
August 2017

Association of dietary cholesterol and egg intakes with the risk of incident dementia or Alzheimer disease: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2017 02 4;105(2):476-484. Epub 2017 Jan 4.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; and

Background: There is little information about the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with the risk of cognitive decline in general populations or in carriers of apolipoprotein E ɛ4 (APO-E4), a major risk factor for dementia.

Objective: We investigated the associations of cholesterol and egg intakes with incident dementia, Alzheimer disease (AD), and cognitive performance in middle-aged and older men from Eastern Finland.

Design: A total of 2497 dementia-free men, aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, were included in the study. Information on the apolipoprotein E (Apo-E) phenotype was available for 1259 men. Data on cognitive performance tests at the 4-y re-examinations were available for 480 men. Dietary intakes were assessed with the use of 4-d food records at baseline. Dementia and AD diagnoses were based on Finnish health registers. Cox regression and ANCOVA were used for the analyses.

Results: During the 21.9-y follow-up, 337 men were diagnosed with dementia, and 266 men were diagnosed with AD. Neither cholesterol nor egg intake was associated with a higher risk of incident dementia or AD. For example, when evaluated continuously, each intake of 100 mg cholesterol/d was associated with a multivariable-adjusted HR of 0.90 (95% CI: 0.79, 1.02) for incident dementia, and each additional 0.5 egg (27 g)/d was associated with an HR of 0.89 (95% CI: 0.78, 1.01). However, egg intake was associated with better performance on neuropsychological tests of the frontal lobe and executive functioning, the Trail Making Test, and the Verbal Fluency Test. The Apo-E4 phenotype did not modify the associations of cholesterol or egg intake (P-interactions > 0.11).

Conclusions: Neither cholesterol nor egg intake is associated with an increased risk of incident dementia or AD in Eastern Finnish men. Instead, moderate egg intake may have a beneficial association with certain areas of cognitive performance.
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http://dx.doi.org/10.3945/ajcn.116.146753DOI Listing
February 2017

Socioeconomic position, John Henryism, and incidence of acute myocardial infarction in Finnish men.

Soc Sci Med 2017 01 25;173:54-62. Epub 2016 Nov 25.

Metabolic Analytical Services Inc., Helsinki, Finland; Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address:

Previous cross-sectional studies examining whether John Henryism (JH), or high-effort coping with socioeconomic adversity, potentiates the inverse association between socioeconomic position (SEP) and cardiovascular health have focused mainly on hypertension in African Americans. We conducted the first longitudinal test of this hypothesis on incident acute myocardial infarction (AMI) using data from the Kuopio Ischemic Heart Disease Risk Factor Study in Finland (N = 1405 men, 42-60 years). We hypothesized that the expected inverse gradient between SEP and AMI risk would be stronger for men scoring high on JH than for those scoring low. John Henryism was measured by a Finnish version of the JH Scale for Active Coping. Four different measures of SEP were used: childhood SEP, education, income, and occupation. AMI hazard ratios (HR) by SEP and JH were estimated using COX proportional hazard models, before and after adjustment for study covariates. 205 cases of AMI occurred over a median of 14.9 years. Men employed in lower rank (farmer, blue-collar) occupations who scored high on JH had significantly higher age-adjusted risks of AMI than men in higher rank (white-collar) occupations (HR = 3.14, 95% CI: 1.65-5.98 for blue collar; HR = 2.33, 95% CI: 1.04-5.22 for farmers) who also scored high on JH. No socioeconomic differences in AMI were observed for men who scored low on JH (HR = 1.36, 95% CI: 0.74-2.47 for blue collar; HR = 0.93, 95% CI: 0.59-1.48 for farmers; p = 0.002 for the SEP × JH interaction). These findings persisted after adjustment for sociodemographic, behavioral, and biological factors. Results for other SEP measures were in the same direction, but did not reach statistical significance. Repetitive high-effort coping with adversity (John Henryism) was independently associated with increased risk for AMI in Finnish men, underscoring the potential relevance of the John Henryism hypothesis to CVD outcomes other than hypertension and to populations other than African Americans.
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http://dx.doi.org/10.1016/j.socscimed.2016.11.034DOI Listing
January 2017

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.

Lancet Diabetes Endocrinol 2016 10 3;4(10):840-9. Epub 2016 Sep 3.

Background: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.

Methods: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.

Findings: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure.

Interpretation: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.

Funding: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035346PMC
http://dx.doi.org/10.1016/S2213-8587(16)30196-6DOI Listing
October 2016

Associations of egg and cholesterol intakes with carotid intima-media thickness and risk of incident coronary artery disease according to apolipoprotein E phenotype in men: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Am J Clin Nutr 2016 Mar 10;103(3):895-901. Epub 2016 Feb 10.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; and.

Background: In general populations, the effects of dietary cholesterol on blood cholesterol concentrations are modest. However, the relation is stronger in those with an ɛ4 allele in the apolipoprotein E gene (APOE). There is little information on the association between cholesterol intake and the risk of coronary artery disease (CAD) among those with the ApoE4 phenotype.

Objective: We investigated the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with carotid intima-media thickness and the risk of incident CAD in middle-aged and older men from eastern Finland.

Design: The study included 1032 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on common carotid artery intima-media thickness (CCA-IMT) were available for 846 men. Dietary intakes were assessed with 4-d food records. Associations with incident CAD and baseline CCA-IMT were analyzed by using Cox regression and ANCOVA, respectively.

Results: The ApoE4 phenotype was found in 32.5% of the men. During the average follow-up of 20.8 y, 230 CAD events occurred. Egg or cholesterol intakes were not associated with the risk of CAD. Each 1 additional egg (55 g)/d was associated with a multivariable-adjusted HR of 1.17 (95% CI: 0.85, 1.61) in the ApoE4 noncarriers and an HR of 0.93 (95% CI: 0.50, 1.72) in the ApoE4 carriers (P-interaction = 0.34). Each 100-mg/d higher cholesterol intake was associated with an HR of 1.04 (95% CI: 0.89, 1.22) in the ApoE4 noncarriers and an HR of 0.95 (95% CI: 0.73, 1.25) in the ApoE4 carriers (P-interaction = 0.81). Egg or cholesterol intakes were also not associated with increased CCA-IMT.

Conclusion: Egg or cholesterol intakes were not associated with increased CAD risk, even in ApoE4 carriers (i.e., in highly susceptible individuals).
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http://dx.doi.org/10.3945/ajcn.115.122317DOI Listing
March 2016

Hydroxyapatite with High Carbonate Substitutions Promotes Osteoclast Resorption through Osteocyte-like Cells.

ACS Biomater Sci Eng 2016 Feb 6;2(2):259-267. Epub 2016 Jan 6.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 1010062, Japan.

The role of ceramic biomaterials in the repair of bone defects varies from materials that purely fill the physical defects of the injured bone to scaffolds that control cellular behaviors. In this study, we investigated the osteoclast formation related to the osteoconductivity of ceramic biomaterials. We performed in vitro cocultures using osteocyte-like cells and bone marrow cells and in vivo implantations of hydroxyapatite with different amounts of carbonate substitutions into rat femurs. The analyses of the cocultures revealed that bone marrow cells differentiated into osteoclasts and were activated to resorb the substratum when grown on hydroxyapatite with higher numbers of carbonate substitutions. This was indicated by the expression of macrophage colony-stimulating factor and receptor activator of the nuclear factor-kappa B ligand that induce osteoclast differentiation by osteocyte-like cells and characteristic resorption pits. The increased osteoclastogenesis in vivo was observed near the hydroxyapatite with more carbonate substitutions after implantation into the rat femurs. These results suggest that the content of carbonate ions in an apatite crystal lattice has an inductive effect on osteoclastogenesis in the vicinity of the implanted ceramic biomaterial. The results contribute to the design of biomaterials that would be resorbed by osteoclasts after fulfilling their primary function as scaffolds for cell growth and eventually bone regeneration.
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http://dx.doi.org/10.1021/acsbiomaterials.5b00509DOI Listing
February 2016

Association of Cardiometabolic Multimorbidity With Mortality.

JAMA 2015 07;314(1):52-60

Portland State University, Portland, Oregon.

Importance: The prevalence of cardiometabolic multimorbidity is increasing.

Objective: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

Design, Setting, And Participants: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

Exposures: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

Main Outcomes And Measures: All-cause mortality and estimated reductions in life expectancy.

Results: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

Conclusions And Relevance: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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http://dx.doi.org/10.1001/jama.2015.7008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664176PMC
July 2015

Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.

PLoS One 2015 2;10(7):e0132321. Epub 2015 Jul 2.

Cardiology Division, Department of Internal Medicine, University of Virginia, Charlottesville, VA, United States of America.

Background: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.

Methods: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.

Results: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.

Conclusion: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489855PMC
May 2016

Common carotid intima-media thickness relates to cardiovascular events in adults aged <45 years.

Hypertension 2015 Apr 26;65(4):707-13. Epub 2015 Jan 26.

From the Department of Radiology (A.L.M.E.), Department of Cardiovascular Epidemiology, Julius Center for Health Sciences and Primary Care (K.A.G., D.E.G., S.A.E.P., M.L.B., H.M.d.R.), and Department of Experimental Cardiology (I.E.H., H.M.d.R.), University Medical Center, Utrecht, Utrecht, The Netherlands; Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Alberta, Canada (T.J.A.); Department of Epidemiology and Public Health University College London, London, United Kingdom (A.R.B.); Department of Clinical Sciences in Malmö, Lund University, Skåne University Hospital, Malmö, Sweden (G.E., B.H., M.R.); Department of Biostatistical Sciences and Neurology, Wake Forest School of Medicine, Winston-Salem, NC (G.W.E.); Division of Vascular Medicine, Department of General Internal Medicine, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands (J.d.G., S.H.); Department of Clinical Epidemiology, University of Malaya Medical Center, Kuala Lumpur, Malaysia (D.E.G.); Osaka Medical Center for Health Science and Promotion, Osaka, Japan (A.I., A.K.); Department of Neurology, Tokyo Women Medical University, Tokyo, Japan (K.K.); Division of Cardiology and Population Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada (E.M.L.); Department of Neurology, University Hospital, Goethe-University, Frankfurt am Main, Germany (M.W.L., M.S.); Brain and Circulation Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway (E.B.M.); Department of General Practice, EMGO Institute, VU Medical Center, Amsterdam, The Netherlands (G.N., J.M.D.); Stroke Center, Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan (S.O.); Department of Radiology, Tufts Medical Center, Boston, MA (D.H.O'L., J.F.P.); Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom (J.F.P., C.R.); Cardiology Division, De

Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavorable risk factor burden.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.04658DOI Listing
April 2015

Low density lipoprotein-containing circulating immune complexes: role in atherosclerosis and diagnostic value.

Biomed Res Int 2014 18;2014:205697. Epub 2014 Jun 18.

Institute of General Pathology and Pathophysiology, Moscow, Russia ; Institute for Atherosclerosis Research, Skolkovo Innovation Center, Moscow, Russia.

It has been suggested that low density lipoprotein-containing circulating immune complexes (LDL-CIC) play a role in atherogenesis and are involved in the formation of early atherosclerotic lesion. These complexes, as well as anti-LDL autoantibodies, have been found in the blood and in the atherosclerotic lesions of patients with different cardiovascular diseases, as well as in the blood of animals with experimental atherosclerosis. It can be suggested that the presence of anti-LDL antibodies in the blood is a result of immune response induced by lipoprotein modification. LDL-CIC differs from native LDL in many aspects. It has much lower sialic acid content, smaller diameter, and higher density and is more electronegative than native LDL. Fraction of LDL-CICs is fundamental to the serum atherogenicity manifested at the cellular level. LDL-CIC, unlike native LDL, is able to induce intracellular accumulation of neutral lipids, especially esterified cholesterol, in cells cultured from uninvolved human aortic intima and in macrophage cultures. After removal of LDL-CIC, the CHD patient's sera lose their atherogenic properties. Titer of LDL-CIC in blood serum significantly correlates with progression of atherosclerosis in human in vivo and has the highest diagnostic value among other measured serum lipid parameters. Elevated CIC-cholesterol might well be a possible risk factor of coronary atherosclerosis.
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http://dx.doi.org/10.1155/2014/205697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087281PMC
October 2015

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies.

PLoS One 2014 14;9(7):e100409. Epub 2014 Jul 14.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably.

Objectives: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.

Data Sources: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE.

Study Eligibility Criteria: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men.

Methods: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied.

Results: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension.

Conclusions: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100409PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096400PMC
April 2016

Glycated hemoglobin measurement and prediction of cardiovascular disease.

JAMA 2014 Mar;311(12):1225-33

National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

Importance: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.

Objective: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.

Design, Setting, And Participants: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.

Main Outcomes And Measures: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk.

Results: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.

Conclusions And Relevance: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
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http://dx.doi.org/10.1001/jama.2014.1873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386007PMC
March 2014

Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration.

Hypertension 2014 Jun 10;63(6):1173-81. Epub 2014 Mar 10.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.02683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523133PMC
June 2014

Fatty acids as determinants of in-vivo lipid peroxidation: the EFFGE study in Eastern Finnish hypertensive and non-hypertensive subjects.

Ann Med 2013 Sep 3;45(5-6):455-64. Epub 2013 Jul 3.

The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland.

Background: The degree of fatty acid (FA) unsaturation as a determinant of lipid peroxidation has been inadequately studied.

Methods: We examined associations of plasma free F2α-isoprostanes (F2-IsoPs), an indicator of in-vivo lipid peroxidation, with the levels/intake of FAs, adjusted for the risk factors of cardiovascular disease (CVD) in 1211 Finnish men and women, of whom 50% were hypertensive, aged 59.3 ± 8.3 years, mean ± SD.

Results: Elevated age- and sex-adjusted plasma free levels of omega-6 and omega-3 polyunsaturated Fas (PUFAs), saturated FAs (SFAs), and the PUFA/SFA and the omega-6/omega-3 PUFA ratios were all associated with decreased F2-IsoPs. High dietary SFA intake was associated with elevated F2-IsoP concentrations. In a multivariable regression (with clinical, nutritional, and behavioral CVD risk factors), female gender, body mass index (BMI), serum apolipoprotein A1, and NT-proBNP (natriuretic peptide) were positively associated with the F2-IsoPs, whereas the dietary PUFA/SFA ratio, plasma β-carotene, the omega-6/omega-3 PUFA ratio, and protein intake showed inverse associations.

Conclusions: We propose that elevated lipid peroxidation is associated with several risk factors of CVD, such as a low PUFA/SFA ratio, whereas the FA precursors of lipid peroxidation, i.e. omega-3 and omega-6 PUFAs are associated with attenuated F2-IsoP levels. These findings provide mechanistic support for earlier observations linking PUFA to improved cardiovascular health.
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http://dx.doi.org/10.3109/07853890.2013.809915DOI Listing
September 2013

Association of mitochondrial genetic variation with carotid atherosclerosis.

PLoS One 2013 9;8(7):e68070. Epub 2013 Jul 9.

Russian Cardiology Research and Production Complex, Moscow, Russia.

In human pathology, several diseases are associated with somatic mutations in the mitochondrial genome (mtDNA). Even though mitochondrial dysfunction leads to increased oxidative stress, the role of mitochondrial mutations in atherosclerosis has not received much attention so far. In this study we analyzed the association of mitochondrial genetic variation with the severity of carotid atherosclerosis, as assessed by carotid intima-media thickness (cIMT) and the presence of coronary heart disease (CHD) in 190 subjects from Moscow, Russia, a population with high CHD occurrence. cIMT was measured by high-resolution B-mode ultrasonography and mtDNA heteroplasmies by a pyrosequencing-based method. We found that heteroplasmies for several mutations in the mtDNA in leukocytes, including C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A mutations, were significantly (p<0.001) associated with both the severity of carotid atherosclerosis and the presence of CHD. These findings indicate that somatic mitochondrial mutations have a role in the development of atherosclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706616PMC
February 2014

Characterization of bone mineral-resembling biomaterials for optimizing human osteoclast differentiation and resorption.

J Biomed Mater Res A 2013 Nov 30;101(11):3141-51. Epub 2013 Mar 30.

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo, 1010062, Japan.

Bioresorption is a biological mechanism by which biomaterials are resorbed and thereby disappear from implantation sites partially or completely over a period of time. Osteoclast-medicated bioresorption is a possible new advantage to incorporate material degradation into remodeling in bone metabolism process. The purpose of this study was to investigate the osteoclastogenesis and bioresorption of synthesized calcium phosphate materials. Differentiation into mature human osteoclasts on carbonated hydroxyapatite (CA) was significantly enhanced compared to hydroxyapatite (HA) and β-tricalcium phosphate, based on the quantitative gene expressions of molecular markers for osteoclast differentiation. Osteoclasts adhered and differentiated into giant multinuclear TRAP-positive cells on every type of synthesized sample based on the histological analysis. Morphological observations using fluorescence and quantitative analysis revealed that the actin rings of osteoclasts on CA were thick, small in diameter and co-localized with vinculin, similar to the rings found on bone slices. In contrast, the actin rings of osteoclasts on HA and culture dishes were thin and large in diameter. Scanning electron microscopic images and quantitative analysis indicated that the resorption pits on CA were significantly deeper than those on HA due to the enhanced tight sealing ability between osteoclasts and their substrate.
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http://dx.doi.org/10.1002/jbm.a.34621DOI Listing
November 2013

C-reactive protein, fibrinogen, and cardiovascular disease prediction.

N Engl J Med 2012 Oct;367(14):1310-20

Background: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events.

Methods: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen.

Results: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years.

Conclusions: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).
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http://dx.doi.org/10.1056/NEJMoa1107477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714101PMC
October 2012

Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.

JAMA 2012 Aug;308(8):796-803

Julius Center for Health Sciences and Primary Care, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Context: The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent.

Objective: To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score.

Data Sources: Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion.

Study Selection: Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke.

Data Extraction: Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease.

Results: We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women.

Conclusion: The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.
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http://dx.doi.org/10.1001/jama.2012.9630DOI Listing
August 2012

Myocardial infarction in relation to mercury and fatty acids from fish: a risk-benefit analysis based on pooled Finnish and Swedish data in men.

Am J Clin Nutr 2012 Oct 15;96(4):706-13. Epub 2012 Aug 15.

Departments of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden.

Background: Exposure to methylmercury from fish has been associated with increased risk of myocardial infarction (MI) in some studies. At the same time, marine n-3 (omega-3) PUFAs are an inherent constituent of fish and are regarded as beneficial. To our knowledge, no risk-benefit model on the basis of data on methylmercury, PUFA, and MI risk has yet been presented.

Objective: The objective of this study was to describe how exposure to both marine n-3 PUFAs and methylmercury relates to MI risk by using data from Finland and Sweden.

Design: We used matched case-control sets from Sweden and Finland that were nested in population-based, prospective cohort studies. We included 361 men with MI from Sweden and 211 men with MI from Finland. MI risk was estimated in a logistic regression model with the amount of mercury in hair (hair-Hg) and concentrations of n-3 PUFAs (EPA and DHA) in serum (S-PUFA) as independent variables.

Results: The median hair-Hg was 0.57 μg/g in Swedish and 1.32 μg/g in Finnish control subjects, whereas the percentage of S-PUFA was 4.21% and 3.83%, respectively. In combined analysis, hair-Hg was associated with higher (P = 0.005) and S-PUFA with lower (P = 0.011) MI risk. Our model indicated that even a small change in fish consumption (ie, by increasing S-PUFA by 1%) would prevent 7% of MIs, despite a small increase in mercury exposure. However, at a high hair-Hg, the modeled beneficial effect of PUFA on MI risk was counteracted by methylmercury.

Conclusions: Exposure to methylmercury was associated with increased risk of MI, and higher S-PUFA concentrations were associated with decreased risk of MI. Thus, MI risk may be reduced by the consumption of fish high in PUFAs and low in methylmercury.
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http://dx.doi.org/10.3945/ajcn.111.033795DOI Listing
October 2012