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Background: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium., Methods: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction., Results: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions., Conclusions: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD., Competing Interests: Disclosures Dr Murphy reports having worked as a consultant for Pharmavite (until 2021). The remaining authors have reported no relationships relevant to the contents of this article. Dr Psaty serves on the steering committee of the Yale Open Data Access Project, funded by Johnson and Johnson.

Background: The effect of marine omega-3 PUFAs on risk of stroke remains unclear., Methods: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome., Results: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P <0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P <0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P =0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P =0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD., Conclusions: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke., Competing Interests: Disclosures Dr O’Keefe reports major ownership interest in Cardiotabs. Dr Harris reports minor ownership interest in Omegaquant Analytics, LLC. Dr Sala-Vila reports travel and grant support from California Walnut Commission. Dr Mora reports compensation for consultant services from Quest Diagnostics. Dr Murphy reports compensation from Pharmavite for consultant services. Dr Bork reports grants from Karen Elise Jensens Fond. Dr Ärnlöv reports compensation from Astellas Pharma for other services; compensation from Boehringer Ingelheim for consultant services; compensation from AstraZeneca for other services; and compensation from Novartis for other services. Dr Geleijnse reports grants from National Institutes of Health to other; grants from Upfield Europe BV to other; and grants from The Dutch Heart Foundation to other. Dr Manson reports grants from National Institutes of Health and compensation from National Institutes of Health for other services. Dr Mora reports compensation from Pfizer for consultant services; employment by Brigham and Women’s Hospital; grants from National Institute of Diabetes and Digestive and Kidney Diseases; and grants from National Heart, Lung, and Blood Institute. Dr Melo van Lent reports grants from National Institutes of Health and grants from Alzheimer’s Association. Dr Mozaffarian reports grants from Rockefeller Foundation; compensation from Beren Therapeutics for other services; stock holdings in HumanCo; compensation from January Inc. for other services; compensation from Filtricine for other services; compensation from Perfect Day for other services; compensation from Tiny Organics for other services; grants from Bill and Melinda Gates Foundation; compensation from Calibrate for other services; grants from Vail Innovative Global Research; grants from Kaiser Permanente Fund at East Bay Community Foundation; compensation from DayTwo for other services; compensation from Instacart health for other services; compensation from Season Health for other services; grants from National Institutes of Health; compensation from Barilla for consultant services; stock holdings in Calibrate; compensation from Kaiser Permanente Fund for other services; compensation from HumanCo for other services

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D)., Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D)., Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background., Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies., Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available)., Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships., Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Background: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association., Methods and Results: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant ( P <5×10 - 8 ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP ), rs7437940 ( AFAP1 ), rs13303 (missense, STAB1 ), and rs1055144 ( 7p15.2 ). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH ) was genome-wide significant., Conclusions: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up., (© 2017 American Heart Association, Inc.)

We describe how hard-of-hearing (HOH) employees renegotiate both their existing and new group memberships when they acquire and begin to use hearing aids (HAs). Our research setting was longitudinal and we carried out a theory-informed qualitative analysis of multiple qualitative data. When an individual discovers that they have a hearing problem and acquire a HA, their group memberships undergo change. First, HOH employees need to start negotiating their relationship with the HOH group. Second, they need to consider whether they see themselves as members of the disabled or the nondisabled employee group. This negotiation tends to be context-bound, situational, and nonlinear as a process, involving a back-and-forth movement in the way in which HOH employees value different group memberships. The dilemmatic negotiation of new group memberships and the other social aspects involved in HA rehabilitation tend to remain invisible to rehabilitation professionals, occupational healthcare, and employers.

Objective: We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region., Approach and Results: We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856)., Conclusions: The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans., Competing Interests: The authors have declared that no conflict of interest exists., (© 2016 American Heart Association, Inc.)

Objective: Despite a wealth of experimental data in animal models, the independent association of insulin resistance with early carotid atherosclerosis in man has not been demonstrated., Approach and Results: We studied a European cohort of 525 men and 655 women (mean age, 44 ± 8 years) free of conditions known to affect carotid wall (diabetes mellitus, hypertension, and dyslipidemia). All subjects received an oral glucose tolerance test, a euglycemic hyperinsulinemic clamp (M/I as a measure of insulin sensitivity), and B-mode carotid ultrasound. In 833 participants (380 men), the carotid ultrasound was repeated after 3 years. In men, baseline intima-media thickness in the common carotid artery (CCA-IMT) was significantly higher (P<0.05) in the lowest M/I tertile, whereas in women CCA-IMT was higher (P<0.0005) in the highest fasting plasma glucose tertile (after adjustment for established risk factors). In multiple regression models, with CCA-IMT as the dependent variable and with risk factors and univariate metabolic correlates as independent variables, circulating free fatty acids and the leptin:adiponectin ratio replaced M/I as independent metabolic determinants of CCA-IMT in men. The strongest metabolic determinant of CCA-IMT in women was fasting plasma glucose. Three-year CCA-IMT changes were not associated with any cardio-metabolic risk factor., Conclusions: In young-to-middle aged apparently healthy people, the association of CCA-IMT with insulin sensitivity and its metabolic correlates differs between men and women. Lower insulin sensitivity is associated with higher IMT only in men; this association seems to be mediated by circulating free fatty acids and adipocytokines. In women, CCA-IMT is independently associated with fasting plasma glucose.

Background: Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS., Methods and Results: A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all 4 study samples (P=7.23×10(-9) in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites (P=0.024-1.88×10(-5)). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status., Conclusions: Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.

Rationale: Isoforms I and II of the glycolytic enzyme hexokinase (HKI and HKII) are known to associate with mitochondria. It is unknown whether mitochondria-bound hexokinase is mandatory for ischemic preconditioning and normal functioning of the intact, beating heart., Objective: We hypothesized that reducing mitochondrial hexokinase would abrogate ischemic preconditioning and disrupt myocardial function., Methods and Results: Ex vivo perfused HKII(+/-) hearts exhibited increased cell death after ischemia and reperfusion injury compared with wild-type hearts; however, ischemic preconditioning was unaffected. To investigate acute reductions in mitochondrial HKII levels, wild-type hearts were treated with a TAT control peptide or a TAT-HK peptide that contained the binding motif of HKII to mitochondria, thereby disrupting the mitochondrial HKII association. Mitochondrial hexokinase was determined by HKI and HKII immunogold labeling and electron microscopy analysis. Low-dose (200 nmol/L) TAT-HK treatment significantly decreased mitochondrial HKII levels without affecting baseline cardiac function but dramatically increased ischemia-reperfusion injury and prevented the protective effects of ischemic preconditioning. Treatment for 15 minutes with high-dose (10 μmol/L) TAT-HK resulted in acute mitochondrial depolarization, mitochondrial swelling, profound contractile impairment, and severe cardiac disintegration. The detrimental effects of TAT-HK treatment were mimicked by mitochondrial membrane depolarization after mild mitochondrial uncoupling that did not cause direct mitochondrial permeability transition opening., Conclusions: Acute low-dose dissociation of HKII from mitochondria in heart prevented ischemic preconditioning, whereas high-dose HKII dissociation caused cessation of cardiac contraction and tissue disruption, likely through an acute mitochondrial membrane depolarization mechanism. The results suggest that the association of HKII with mitochondria is essential for the protective effects of ischemic preconditioning and normal cardiac function through maintenance of mitochondrial potential.

Objective: Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism., Methods and Results: Our data show that rs7575840 is associated with serum apoB levels (P=4.85×10(-10)) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (P=2×10(-5) to 9×10(-7)) in the Finnish Metabolic Syndrome in Men study sample (n=7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (n=2666, P=3.33×10(-5)). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (P=1.13×10(-10)) and a regional noncoding RNA (BU630349) (P=7.86×10(-6)) in adipose tissue., Conclusions: It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels.

Rationale: Cardiomyocytes switch substrate utilization from fatty acid to glucose under ischemic conditions; however, it is unknown how perturbations in glycolytic enzymes affect cardiac response to ischemia/reperfusion (I/R). Hexokinase (HK)II is a HK isoform that is expressed in the heart and can bind to the mitochondrial outer membrane., Objective: We sought to define how HKII and its binding to mitochondria play a role in cardiac response and remodeling after I/R., Methods and Results: We first showed that HKII levels and its binding to mitochondria are reduced 2 days after I/R. We then subjected the hearts of wild-type and heterozygote HKII knockout (HKII(+/)⁻) mice to I/R by coronary ligation. At baseline, HKII(+/)⁻ mice have normal cardiac function; however, they display lower systolic function after I/R compared to wild-type animals. The mechanism appears to be through an increase in cardiomyocyte death and fibrosis and a reduction in angiogenesis; the latter is through a decrease in hypoxia-inducible factor-dependent pathway signaling in cardiomyocytes. HKII mitochondrial binding is also critical for cardiomyocyte survival, because its displacement in tissue culture with a synthetic peptide increases cell death. Our results also suggest that HKII may be important for the remodeling of the viable cardiac tissue because its modulation in vitro alters cellular energy levels, O₂ consumption, and contractility., Conclusions: These results suggest that reduction in HKII levels causes altered remodeling of the heart in I/R by increasing cell death and fibrosis and reducing angiogenesis and that mitochondrial binding is needed for protection of cardiomyocytes.

Objective: Activating transcription factor 6 (ATF6) is a sensor of the endoplasmic reticulum stress response and regulates expression of several key lipogenic genes. We used a 2-stage design to investigate whether ATF6 polymorphisms are associated with lipids in subjects at increased risk for cardiovascular disease (CVD)., Methods and Results: In stage 1, 13 tag-SNPs were tested for association in Dutch samples ascertained for familial combined hyperlipidemia (FCHL) or increased risk for CVD (CVR). In stage 2, we further investigated the SNP with the strongest association from stage 1, a Methionine/Valine substitution at amino-acid 67, in Finnish FCHL families and in subjects with CVR from METSIM, a Finnish population-based cohort. The combined analysis of both stages reached region-wide significance (P=9 x 10(-4)), but this association was not seen in the entire METSIM cohort. Our functional analysis demonstrated that Valine at position 67 augments ATF6 protein and its targets Grp78 and Grp94 as well as increases luciferase expression through Grp78 promoter., Conclusions: A common nonsynonymous variant in ATF6 increases ATF6 protein levels and is associated with cholesterol levels in subjects at increased risk for CVD, but this association was not seen in a population-based cohort. Further replication is needed to confirm the role of this variant in lipids.

Objective: There is increasing physiological evidence in rodents connecting the neuropeptide galanin to triglyceride (TG) levels. We hypothesized that variation in the galanin preproprotein (GAL) gene may contribute to hypertriglyceridemia (HTG) in humans., Methods and Results: We investigated GAL as a TG candidate gene by genotyping 4 tagSNPs in Dutch, Finnish, and Mexican familial combined hyperlipidemia (FCHL) families as well as in white combined hyperlipidemia cases/controls (n=2471). The common allele of rs2187331, residing in the promoter region of GAL, was significantly associated with HTG (probability value=0.00038). In an unascertained population sample of 4463 Finnish males, the rare allele of rs2187331 was associated with higher TGs (probability value=0.0028 to 0.00016). We also observed an allele specific difference with rs2187331 in reporter gene expression and nuclear factor binding in vitro. Furthermore, we detected differential expression of many key lipid genes in adipose tissue based on rs2187331 genotypes., Conclusions: The SNP rs2187331 is associated with HTG in FCHL and white combined hyperlipidemia cases/controls and influences TG levels in the population. Further studies are warranted to elucidate the allelic difference observed between FCHL and the general population. Functional evidence shows that rs2187331 has an allele specific cis-regulatory function and influences the expression of lipid related genes in adipose.

Background and Purpose: Limited information is available on the role of the metabolic syndrome (MetS) to predict stroke. We investigated the relationship of the MetS and its single components, defined by 6 different criteria, with stroke in a prospective population-based study., Methods: The MetS was defined according to the World Health Organization, the European Group for the Study of Insulin Resistance, the National Cholesterol Education Program (NCEP), the American College of Endocrinology, the International Diabetes Federation, and the American Heart Association (updated NCEP) criteria. We investigated the relationship of the MetS with stroke using Cox regression analyses in 991 Finnish subjects without diabetes, aged 65 to 74 years at baseline, and followed-up for 14 years., Results: The MetS defined by the World Health Organization, European Group for the Study of Insulin Resistance, NCEP, International Diabetes Federation, and updated NCEP criteria was significantly associated with incident stroke (fatal and nonfatal) when adjusted for confounding variables (HR, 1.52 to 1.72). After exclusion of subjects with myocardial infarction, these 5 definitions still predicted stroke (HR, 1.49 to 1.80). Of the single components of the MetS, the following predicted stroke in multivariable models when subjects with myocardial infarction were excluded: impaired glucose tolerance (2-hour glucose in an oral glucose tolerance test, 7.8 to 11.0 mmol/L) by the World Health Organization and American College of Endocrinology criteria (HR, 1.66); insulin resistance (HR, 1.60) by the European Group for the Study of Insulin Resistance criteria; and central obesity (HR, 1.52) by the NCEP criteria., Conclusions: The MetS defined by the 6 criteria except for the American College of Endocrinology definition predicts stroke in elderly subjects. However, impaired glucose tolerance alone is as strong a predictor of stroke as is the MetS defined by the World Health Organization, NCEP and updated NCEP criteria.

Purpose: To study the associations of seven single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor gamma (PPARG) gene with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes (T2D), and the interactions of the SNPs with physical activity (PA)., Methods: Overweight individuals with IGT who participated in the Finnish Diabetes Prevention Study (DPS) (N = 479) were followed, on average, 4.2 yr. PA was assessed yearly with a 12-month validated questionnaire., Results: In Cox regression analyses, the rare alleles of rs17036314 and rs1801282 (Pro12Ala) predicted conversion to T2D (P = 0.038 and 0.037, respectively), but only rs17036314 predicted T2D after adjustment for baseline fasting glucose (P = 0.030). The change in the total amount of PA, stratified by median, modified the association of rs17036314 and rs1801282 with the risk of T2D during the intervention (P = 0.002 and 0.031, respectively, for interaction between PA change and genotype); an increase in PA seemed to remove the effect of the risk alleles. The distinct rs1152003 polymorphism interacted with the study group on the conversion to T2D (P = 0.027) and tended to increase the risk of T2D in the intervention group (P = 0.050). No interaction between rs1152003 and the change in PA was found., Conclusions: The rs17036314, rs1801282 (Pro12Ala), and rs1152003 were associated with the risk of T2D in the DPS. Increased PA seemed to decrease the effect of the risk alleles of rs17036314 and rs1801282 on the conversion to T2D. The effect of rs1152003 was modified by other lifestyle changes or the lifestyle intervention as a whole.

No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor-deficient mice synthetizing only apolipoprotein B100 (LDLR(-/-) ApoB(100/100)). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR(-/-)ApoB(100/100) mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR(-/-)ApoB(100/100) controls. In addition, old IGF-II/LDLR(-/-)ApoB(100/100) mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR(-/-)ApoB(100/100) mice did not differ from LDLR(-/-)ApoB(100/100) controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.

Objective: To investigate whether the association between insulin resistance (IR) and depressive symptoms is present already in young adult males. The association between IR and depression has been poorly studied, although the existence of a connection of Type II diabetes with depression is well established. We previously demonstrated at epidemiological level in two groups of men aged 31 years and 61 to 63 years that IR is linked with depressive symptoms., Methods: In a cross-sectional study, involving 1054 healthy Finnish male military conscripts of about 19 years of age, IR was defined through homeostasis model assessment (HOMA-IR). The severity of the depressive symptoms was evaluated through a Finnish modification of the 13-item Beck Depression Inventory (R-BDI). Moderate-to-severe depressive symptoms were said to be present, if the R-BDI score was > or = 8, and mild depressive symptoms were present if the R-BDI score was 5 to 7., Results: After adjusting for confounders, moderate-to-severe depressive symptoms increased the risk for IR, as defined by the highest decile of the HOMA-IR, up to 2.8-fold (odds ratio = 2.8; 1.2-6.5). Mild depressive symptoms were not significantly associated with IR., Conclusions: In young adult males, co-occurring strictly defined IR seems to be positively associated with current moderate-to-severe depressive symptoms.

Objective: To assess the association of metabolic syndrome (MetS) with Alzheimer disease (AD)., Methods: The authors derived subjects from a population-based study of 980 randomly selected elderly subjects. After exclusion of all non-Alzheimer dementia cases, the final study population included 959 subjects (337 men and 622 women) aged 69 to 78 years. The presence of MetS was defined according to the National Cholesterol Education Program (Adult Treatment Panel III) criteria, and the diagnosis of AD was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association., Results: Of the study subjects, 418 (43.6%) had MetS. Probable or possible AD was diagnosed in 45 subjects (4.7%). AD was more frequently detected in subjects with MetS than in subjects without MetS (7.2 vs 2.8%; p < 0.001). The prevalence of AD was higher in women with MetS vs women without the syndrome (8.3 vs 1.9%; p < 0.001), but in men with MetS, the prevalence of AD was not increased (3.8 vs 3.9%; p = 0.994). In univariate logistic regression analysis, MetS was significantly associated with AD (odds ratio [OR] 2.71; 95% CI 1.44 to 5.10). In multivariate logistic regression analysis including also apolipoprotein E4 phenotype, education, age, and total cholesterol, MetS was significantly associated with AD (OR 2.46; 95% CI 1.27 to 4.78). If only nondiabetic subjects were included in the multivariate analysis, MetS was still significantly associated with AD (OR 3.26; 95% CI 1.45 to 7.27)., Conclusion: Metabolic syndrome is associated with Alzheimer disease in elderly subjects.

Background: Advanced glycation end products (AGEs), modification products of glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes as well as in nondiabetic subjects., Methods and Results: Serum levels of AGEs were measured with an immunoassay in samples obtained at baseline examination of a random sample of 1141 nondiabetic individuals (535 men and 606 women), aged 45 to 64 years, living in Kuopio, East Finland, or Turku, West Finland in 1982 to 1984. After 18 years of follow-up, all-cause mortality, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality were registered on the basis of copies of death certificates. Multivariate Cox regression model showed a significant association of serum AGEs with all-cause (P=0.012), CVD (P=0.018), and CHD (P=0.008) mortality in women but not in men. Fasting serum AGEs in the highest quartile were an independent risk factor for all-cause (hazards ratio [HR], 1.90; 95% CI, 1.16 to 3.11; P=0.011) and CHD (HR, 6.51; 95% CI, 1.78 to 23.79; P=0.005) mortality in women, even after the adjustment for confounding factors, including highly sensitive C-reactive protein., Conclusions: The present study is the first to show that serum levels of AGEs can predict total, CVD, and CHD mortality in nondiabetic women.

Background: Detailed metabolic defects in glucose and energy metabolism and abnormalities in a variety of cardiovascular risk factors are largely unknown in subjects with the metabolic syndrome., Methods and Results: We characterized the metabolic syndrome in 119 nondiabetic offspring of diabetic probands. Cardiovascular risk factors, including cytokines and adhesion molecules, were measured. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp and indirect calorimetry; intra-abdominal fat and subcutaneous fat were assessed by CT; and maximal oxygen consumption was measured with a bicycle ergometer test. By applying factor analysis, we identified a single factor, the metabolic syndrome factor, from the following variables: 2-hour glucose, fasting insulin, body mass index, waist, HDL cholesterol, triglycerides, and mean blood pressure. Subjects with the highest factor score were defined as having the metabolic syndrome. During hyperinsulinemia, the highest factor score was associated with decreased rates of glucose oxidation and nonoxidative glucose disposal, high rates of lipid oxidation, low energy expenditure, and impaired suppression of free fatty acids during hyperinsulinemia. Furthermore, the metabolic syndrome was associated with a high amount of visceral fat, hypoadiponectinemia, a low maximum oxygen uptake, and high levels of C-reactive protein, proinflammatory cytokines, and adhesion molecules., Conclusions: The metabolic syndrome is characterized by an excess of intra-abdominal fat, hypoadiponectinemia, insulin resistance in skeletal muscle and adipose tissue, multiple defects in glucose and energy metabolism, and elevated levels of cytokines and adhesion molecules.

Purpose of Review: Both insulin resistance and dyslipidaemia are determined by genetic and environmental factors. Depending on their expression and their function, gene variants (mutations, polymorphisms) can primarily regulate either insulin action or dyslipidaemia. The purpose of this review is to give some examples from recent studies on gene variants regulating primarily insulin signalling or lipoprotein metabolism., Recent Findings: Common polymorphisms in the PC-1, insulin receptor substrate 1 and 2, and PPAR-gamma 2 genes have been linked to insulin resistance and dyslipidaemia, although the results have not been consistent. However, the Pro12Pro genotype of the PPAR-gamma 2 gene has been consistently associated with insulin resistance and the risk of type 2 diabetes. Promoter polymorphisms in the hepatic lipase gene, the 54Thr allele of the fatty acid binding protein 2 gene, and genes regulating LDL particle size have been associated with lipid metabolism, but on the other hand their association with insulin resistance is not consistent., Summary: Although results have not always been consistent, gene variants affecting primary insulin action or dyslipidaemia, and particularly their interaction with the environment, are important modulators of glucose and lipoprotein metabolism.

Background: Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF gene transfer given during angioplasty (PTCA) and stenting., Methods and Results: Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58+/-6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2x10(10) pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 microg of DNA with 2000 microL of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringer's lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups., Conclusions: Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.

Context: The association of androgenic alopecia (AGA) with insulin resistance, coronary artery disease and hypercholesterolemia has been previously reported in men, but no such association has been reported in women with female androgenic alopecia (AGA). Female AGA has usually been linked with hyper-androgenism and hirsutism and, most recently, also with polycystic ovarian syndrome (PCOS), even though epidemiological documentation of the latter association is scanty. Polycystic ovarian syndrome is quite common among Caucasian women, and its association with insulin resistance is well documented., Objectives and Design: The aim of this study was to obtain a more precise estimation of the prevalence on female AGA and to describe its possible connections with insulin resistance linked parameters and with paternal and maternal family history of alopecia. A cross-sectional population based cohort survey was carried out in the City of Oulu, Finland in 1998., Setting and Participants: As a part of a population based cohort study the hair status of 324 women aged 63 years was assessed by a modification of Ludwig's scale. The background data consisting of anthropometric measures (weight, height, body mass index, waist, hip and neck circumferences), smoking status, chronic diseases and their medication as well as the family history of AGA were collected by questionnaires and interviews made by study nurses and in clinical examination. Blood samples for laboratory tests were taken on the same occasion., Results: The prevalence of extensive loss of hair (at least grade II or III on Ludwig's scale) was quite high (31.2%). The insulin resistance associated parameters, such as waist and neck circumferences, abdominal obesity measured by waist-to-hip ratio, mean insulin concentration (11.3 mU/l versus 9.95 mU/l, p=0.02) or urinary albumin-to-creatinine ratio (1.80 versus 1.58, p=0.01), were significantly higher in women with extensive hair loss compared to those with normal hair or only minimal hair loss (grade I on Ludwig's scale). The women belonging to the highest quintiles of neck or waist circumferences had significantly increased risk for extensive hair loss compared to those with normal hair or minimal hair loss, the unadjusted ORs being 2.25 (95% CI, 1.26-4.03) and 1.75 (95% CI, 1.00-3.07), respectively. Similarly in women with hyperinsulinemia (fs-insulin >10 mU/l), microalbuminuria (urinary albumin-to-creatinine ratio exceeding the highest microalbuminuria decile (>2.5 mg/mmol) and paternal history of AGA the ORs for alopecia were increased being 1.65 (95% CI, 1.02-2.67), 2.39 (95% CI, 1.21-4.73) and 2.08 (95% CI, 1.26-3.44). All of these ORs, except those for highest quintiles of waist and neck circumferences remained significant in multiple adjusted models., Conclusions: According to the results of this study, female AGA (grade II or III on Ludwig's scale) was quite common among Finnish women aged 63 years. Our results support the hypothesis that women with some markers of insulin resistance have significantly increased risk for female AGA. Paternal history of alopecia seemed to be more common in female AGA compared to women with normal or minimal loss of hair.

Coronary heart disease (CHD) is a multifactorial disease caused by environmental and genetic factors. CHD clusters in families, but it is not known whether susceptibility to early-onset CHD is associated with the clustering of cardiovascular risk factors. Therefore, we determined the levels of cardiovascular risk factors among siblings with and without severe early-onset CHD drawn from 101 Finnish families. Probands with CHD, compared with their siblings without CHD, had, respectively, higher 2-hour insulin levels (475.7 versus 331.8 pmol/L, P=0.011) and 2-hour insulin areas (796.2 versus 640.4 pmol/L per hour, P=0.031) in an oral glucose tolerance test, lower high density lipoprotein cholesterol levels (1.22 versus 1.42 mmol/L, P=0.001), higher total triglyceride levels (1.91 versus 1.68 mmol/L, P=0.018), higher very low density lipoprotein triglyceride levels (1.25 versus 1.06 mmol/L, P=0.011), and higher fibrinogen levels (3.8 versus 3.4 g/L, P= 0.008). No significant differences were found in cardiovascular risk factors between affected siblings and probands with CHD. Environmental or lifestyle factors did not differ between siblings with or without early-onset CHD. We conclude that cardiovascular risk factors associated with the insulin resistance syndrome (hyperinsulinemia, low high density lipoprotein cholesterol, high total and very low density lipoprotein triglycerides, and high fibrinogen) are likely to contribute indirectly to early-onset CHD.

Objective: To investigate whether the APOE-epsilon4 allele is associated with weight loss in patients with AD or in nondemented elderly subjects., Background: Weight loss has been considered a typical feature of AD. APOE-epsilon4 is a risk factor for AD and was recently proposed to be associated with weight loss in elderly women. It is not known whether APOE-epsilon4 is associated with weight loss in patients with AD or in the general population., Methods: Weight and BMI measurements at an average interval of 3.5 years and APOE phenotype determination were performed in an elderly population (n = 980), including 46 patients with AD and 911 control subjects at the end of the follow-up., Results: On average, patients with AD with the epsilon4 allele lost 1.9 +/- 4.0 kg (BMI 0.8 +/- 1.8 kg/m2) whereas epsilon4 noncarriers gained 1.2 +/- 3.8 kg (BMI 0.4 +/- 1.5 kg/m2) (both p < 0.05), after controlling for diabetes and exercise. However, when men and women were analyzed separately, weight loss was observed only in those women with AD with the epsilon4 allele. Clinically significant weight loss, defined as loss of > or = 5% of body weight, occurred more frequently in both patients with AD (30% versus 6%; p < 0.05) and control subjects (28% versus 18%; p < 0.001) carrying the epsilon4 allele., Conclusions: The APOE-epsilon4 allele may contribute to the unexplained weight loss in AD, especially in women.

Low activity of hepatic lipase (HL) has been associated with high levels of triglycerides and high density lipoproteins, but the association of the HL promoter variants with insulin sensitivity has not been investigated. Therefore, in this study, the relationship of the G-250A promoter variant of the HL gene to the rates of insulin-stimulated glucose uptake measured by the hyperinsulinemic euglycemic clamp was investigated in 110 control subjects (82 men and 28 women, aged 50.7+/-7.6 [mean+/-SD] years, body mass index 26. 1+/-3.6 kg/m(2)) and in 105 first-degree relatives (65 men and 40 women, aged 47.8+/-16.0 years, body mass index 26.9+/-5.3 kg/m(2)) of 34 families with familial combined hyperlipidemia (FCHL). The A-250 allele of the HL promoter was associated with low rates of insulin-stimulated whole-body nonoxidative glucose disposal in control subjects (41.1+/-12.7 micromol. kg(-1). min(-1) in subjects with the G-250G genotype, 36.9+/-13.1 micromol. kg(-1). min(-1) in subjects with the G-250A genotype, and 29.9+/-13.5 micromol. kg(-1). min(-1) in subjects with the A-250A genotype; P=0.012 adjusted for age and sex) and with low rates of insulin-stimulated whole-body glucose oxidation in FCHL family members (16.7+/-4.2 versus 15.0+/-4. 4 versus 14.1+/-4.4 micromol. kg(-1). min(-1), P=0.024). In addition, the A-250 allele was associated with high levels of fasting insulin (P=0.047), very low density lipoprotein cholesterol (P=0.007), and total (P=0.009) and very low density lipoprotein (P=0.005) triglycerides in control subjects and with high levels of low density lipoprotein triglycerides (P=0.001) in FCHL family members (n=340). We conclude that the G-250A promoter variant of the HL gene is associated with dyslipidemia and insulin resistance. Mechanisms via which this polymorphism could affect insulin sensitivity remain to be elucidated.

The interpretation of conventional multivariate analyses concerning the relation of insulin to the risk of atherosclerotic disease is complex because of correlations of insulin with other risk factors. Therefore, we applied factor analysis to study the clustering of risk factors in the baseline data of the Helsinki Policemen Study (970 healthy men aged 34 to 64 years) and investigated whether these clusterings predict coronary heart disease (CHD) and stroke risk. Areas under the glucose and insulin response curves (AUC glucose and AUC insulin) were used to reflect glucose and insulin levels during oral glucose tolerance tests. During the 22-year follow-up, 164 men had a CHD event, and 70 men had a stroke. Factor analysis of 10 risk factor variables produced 3 underlying factors: insulin resistance factor (comprising body mass index, subscapular skinfold, AUC insulin, AUC glucose, maximal O(2) uptake, mean blood pressure, and triglycerides), lipid factor (cholesterol and triglycerides), and lifestyle factor (physical activity and smoking). In multivariate Cox models, the age-adjusted hazard ratio for insulin resistance factor during the 22-year follow-up was 1.28 (95% CI 1.10 to 1.50) with regard to CHD risk and 1.64 (95% CI 1.29 to 2.08) with regard to stroke risk. Lipid factor predicted the risk of CHD but not that of stroke, and lifestyle factor predicted a reduced CHD risk. Factor analysis including only 6 risk factor variables proposed to be central components of insulin resistance syndrome (body mass index, subscapular skinfold, AUC insulin, AUC glucose, mean blood pressure, and triglycerides) produced only a single insulin resistance factor that predicted the risk of CHD and stroke independently of other risk factors.

Insulin resistance has been associated with hypertriglyceridemia, combined hyperlipidemia, and familial combined hyperlipidemia (FCHL). Whether all FCHL patients with different types of dyslipidemia have low insulin sensitivity has not been evaluated. We measured insulin sensitivity by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 110 healthy controls and in 105 nondiabetic, FCHL family members: in 50 without dyslipidemia, in 19 with hypercholesterolemia (total cholesterol >/=7.7 mmol/L), in 22 with hypertriglyceridemia (total triglycerides >/=2.4 mmol/L in men 2.4 mmol/L in women), and in 14 with combined hyperlipidemia. During the hyperinsulinemic clamp, FCHL family members had higher free fatty acid levels than did controls (0.06+/-0.06 [mean+/-SD] in controls versus 0.16+/-0.11 in relatives without dyslipidemia versus 0.15+/-0. 07 in hypercholesterolemic patients versus 0.29+/-0.14 in hypertriglyceridemic patients versus 0.27+/-0.17 mmol/L in patients with combined hyperlipidemia; P<0.001 after adjustment for age, sex, and body mass index). Relatives without dyslipidemia (16.4+/-4.4 micromol. kg(-1). min(-1), P=0.001) and patients with hypertriglyceridemia (12.8+/-3.8 micromol. kg(-1). min(-1), P<0.001) and with combined hyperlipidemia (13.7+/-3.1 micromol. kg(-1). min(-1), P<0.001) had lower rates of insulin-stimulated glucose oxidation than did controls (19.4+/-4.7 micromol. kg(-1). min(-1)). Also, the rates of nonoxidative glucose disposal were lower in patients with hypertriglyceridemia (P=0.001) and combined hyperlipidemia (P=0.011) than in controls. In contrast, subjects with hypercholesterolemia and control subjects had similar rates of insulin-stimulated glucose uptake. We conclude that a defect in free fatty acid suppression during hyperinsulinemia, probably located in adipose tissue, is characteristic for all FCHL patients with varying types of dyslipidemia, whereas insulin resistance in skeletal muscle is observed only in FCHL patients with elevated triglyceride levels.

A predominance of small, dense, low density lipoprotein (LDL) particles has consistently been associated with coronary heart disease (CHD) in young and middle-aged subjects in cross-sectional studies. Recently, 3 prospective, case-control studies showed that decreased LDL size is a predictor of CHD in middle-aged subjects. However, it is not known whether decreased LDL size is mainly associated with premature CHD or whether it continues to play a role in CHD risk at older ages also. We performed a prospective, nested case-control study in 86 subjects (58 nondiabetic and 28 type 2 diabetic) aged 65 to 74 years who were free of myocardial infarction at baseline and who then had a myocardial infarction or CHD death during a 3.5-year follow-up (cases) and in 172 controls matched for sex and diabetes status but who remained free of CHD during follow-up. LDL particle size determined by gradient gel electrophoresis (268.2+/-0.9 versus 268.5+/-0.7 A, P=0.782) and the proportion of subjects with LDL subclass phenotype B (20.9 versus 21. 5, P=0.914) were similar among cases and controls. Furthermore, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A(1), fasting glucose, fasting insulin, waist-to-hip ratio, and body mass index were not associated with CHD risk. However, smoking and increased systolic blood pressure, apolipoprotein B levels, and the total cholesterol-high density lipoprotein cholesterol ratio were significant predictors of CHD events both in univariate and multivariate analyses. Our findings indicate that LDL size is not a predictor of CHD events in elderly white subjects after controlling for diabetes status.

Objective: To assess the the effect of antiplatelet therapy on the severity of subsequent stroke in patients with stroke and TIA., Background: The Second European Stroke Prevention Study (ESPS2) recruited 6,602 patients in four treatment groups: placebo, 2 x 25 mg acetylsalicylic acid (ASA), 2 x 200 mg dipyridamole (DP), and the combination of 50 mg ASA and 400 mg DP per day. Seventy-six percent of the patients had had a stroke as the qualifying event, whereas 24% had a TIA. All patients were followed at 3-month intervals for 2 years. ESPS2 showed a benefit from antiplatelet treatment compared with placebo and an additional benefit using ASA and DP together compared with either of these antiplatelet agents alone., Methods: In the ESPS2, the study protocol included assessment of severity of end point stroke with the modified Rankin scale once the stroke had clinically stabilized, and no further impairment was observed. There were 824 new stroke events during follow-up. In 701 of them, the initial Rankin scale was known, and this was also evaluated after each nonfatal recurrent stroke. The difference in Rankin scale between treatment groups was analyzed after recurrent stroke, and the progress in Rankin scale between entry and recurrent stroke was quantified by calculating the number of patients with a change of one or more degrees in the scale., Results: There were no significant differences in these changes in Rankin scale between the treatment groups. The mean time to reach an end point of stroke was longest in patients who used ASA + DP (p = 0.057). However, there was no difference among the treatment groups in the time to death during follow-up., Conclusion: This study suggests that antiplatelet therapy does not influence the severity of recurrent stroke as evaluated with the Rankin scale. However, antiplatelet therapy seems to lengthen the time the patient remains free from a recurrent stroke.

Background: The role of a cluster of risk factors characteristic for the insulin resistance syndrome as a predictor for coronary heart disease (CHD) has not been studied previously., Methods and Results: Clustering of cardiovascular risk factors was analyzed by factor analysis to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) in a nondiabetic population of 1069 subjects 65 to 74 years old from eastern Finland followed up for 7 years. There were 151 CHD events (92 for men, 59 for women) during the follow-up period. In men, factor 1 (the insulin resistance factor, which reflected primarily body mass index, waist-to-hip ratio, triglycerides, fasting plasma glucose, and insulin) (hazards ratio [HR] with 95% CI, 1.33, CI 1.08, 1.65, P=0.008), factor 2 (alcohol consumption, high HDL cholesterol, low triglycerides) (HR 0.78, CI 0.63, 0.96, P=0.020), factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR 1.52, CI 1.26, 1.83, P<0.001), and factor 4 (high total cholesterol and triglycerides) (HR 1.42, CI 1. 15, 1.77, P=0.002) predicted CHD events in multivariate Cox regression analysis. In women, the insulin resistance factor did not predict CHD events (HR 1.06, CI 0.82, 1.36), but factor 2 (previous stroke, low HDL cholesterol and high triglycerides) (HR 1.34, CI 1. 06, 1.69, P=0.014) and factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR 1.44, CI 1.15, 1.82, P=0.002) predicted CHD events., Conclusions: Our study supports the notion that the insulin resistance syndrome is a risk factor for CHD in elderly men.

Patients with type 1 diabetes mellitus, especially those with nephropathy, are at increased risk for coronary heart disease (CHD). However, information on the predictive value of cardiovascular risk factors and the degree of hyperglycemia with respect to CHD events in patients with type 1 diabetes without nephropathy is still incomplete. Therefore, we performed a prospective study on risk factors for CHD in patients with type 1 diabetes free of clinical nephropathy. At baseline examination, cardiovascular risk factor levels of CHD were determined in 177 patients with type 1 diabetes (87 men and 90 women), age 45 to 64 years at baseline and >/=30 years at the time of diagnosis of diabetes. These patients were followed up to 7 years with respect to CHD events. Altogether, 20 patients with type 1 diabetes (13 men [7.3%] and 7 women [3.9%]) died of CHD and 28 patients with type 1 diabetes (17 men [9.6%] and 11 women [6.2%]) had a serious CHD event (death from CHD or nonfatal myocardial infarction). In multivariate Cox regression analysis, a previous history of myocardial infarction (hazard ratio [HR] and its 95% confidence interval, 8.0 [3.1 to 21.0], P<0.001), high glycohemoglobin A1 (>10.4%, the highest tertile, HR 5.4 [1.4 to 20.4], P=0.013), and the duration of diabetes (>16 years, the highest tertile, HR 4.2 [1.3 to 12.9], P=0.013) were the only variables associated with CHD death even after adjustment for other cardiovascular risk factors. These variables also predicted the incidence of all CHD events. Our results indicate that poor metabolic control is a strong predictor of CHD events in patients with late-onset type 1 diabetes without nephropathy, independently of other cardiovascular risk factors.

Polymorphism of the fatty acid-binding protein 2 (FABP2) gene has been shown to affect the affinity of intestinal FABP for fatty acids. This could cause changes in postprandial triglyceride metabolism. In the present study, postprandial lipemia was studied in normotriglyceridemic subjects with genetic variation in the FABP2 gene. Oral fat-loading tests were performed in 8 subjects homozygous for the Thr-encoding allele at codon 54 of the FABP2 gene and in 7 subjects homozygous for the Ala-encoding allele (wild type). There were no significant differences between these 2 groups in age, body mass index, fasting plasma triglyceride and cholesterol levels, or fasting glucose and insulin levels. The increase of plasma triglyceride concentration after the fat test meal was significantly greater in subjects who were homozygous for the Thr-54 allele (area under the response curve, 4.27+/-1.31 versus 2.49+/-1.18 mmol/L x h-1, P=0.04). The difference was seen in both chylomicron (2.51+/-0. 98 versus 1.41+/-0.74 mmol/L x h-1, P=0.03) and very low-density lipoprotein triglycerides (1.57+/-0.77 versus 0.99+/-0.40 mmol/L x h-1, P=0.04). Postprandial triglyceride response correlated with fasting triglycerides in the Ala-54 homozygotes (r=0.79, P=0.05) but not in the Thr-54 homozygotes (r=0.09), who showed a strong correlation between triglyceride and insulin responses (r=0.83, P=0. 02). With reservations related to a small number of subjects studied, these results indicate that the Thr-encoding allele of the FABP2 gene is associated with increased postprandial lipemia. The lipemic response was associated with postprandial insulin response, suggesting that in the Thr-54 homozygotes, altered postprandial lipemia may also modify insulin action or vice versa.

Familial combined hyperlipidemia (FCHL) is characterized by hyperlipidemia and insulin resistance, but intracellular defect in insulin action is unknown. Therefore, we investigated insulin action by applying the hyperinsulinemic euglycemic clamp technique with indirect calorimetry in 58 FCHL family members (28 with FCHL; 30 without dyslipidemia; aged 49+/-12 years; body mass index [BMI], 25. 2+/-4.0 kg/m2) and in 72 healthy control subjects (aged 54+/-6 years; BMI, 26.3+/-3.1 kg/m2). In the fasting state, FCHL patients had higher levels of total cholesterol, total triglycerides, and apolipoprotein B than control subjects (P<0.001 after adjustment for gender, age, and BMI). During the euglycemic clamp, FCHL patients had lower rates of glucose oxidation (15.93+/-3.55 versus 19.65+/-4. 60 micromol/kg/min; P=0.001) and higher rates of lipid oxidation (0. 15+/-0.13 versus 0.01+/-0.25 mg/kg/min; P=0.024), as well as higher levels of serum-free fatty acids (FFA) (0.24+/-0.17 versus 0.06+/-0. 06 mmol/L; P<0.001) compared with those of control subjects. Relatives without dyslipidemia differed similarly from control subjects with respect to rates of glucose and lipid oxidation and FFA suppression during the hyperinsulinemic clamp. In FCHL family members, during the euglycemic clamp FFAs correlated negatively with the rates of glucose oxidation (P<0.001) but not with the rates of glucose nonoxidation (P=0.408). In FCHL family members without dyslipidemia and in control subjects, FFAs during the clamp correlated positively with levels of total triglycerides (P<0.001) and very low density lipoprotein cholesterol (P=0.008). We conclude that in patients with FCHL, and also in their first-degree relatives, insulin's suppressive effect on FFA levels is impaired, which may precede dyslipidemia in FCHL.

Background and Purpose: Several studies have shown that hyperinsulinemia is associated with the risk of coronary heart disease, but information on the association of hyperinsulinemia with the risk of stroke is limited. We investigated the association of hyperinsulinemia with the risk of stroke during a 22-year follow-up of the Helsinki Policemen Study population., Methods: The study was based on a cohort of 970 men aged 34 to 64 years who were free of cerebrovascular disease, other cardiovascular disease, or diabetes. Risk factor measurements at baseline examination included an oral glucose tolerance test with blood glucose and plasma insulin measurements at 0, 1, and 2 hours. Area under the insulin response curve during oral glucose tolerance test was used as a composite variable reflecting plasma insulin levels., Results: During the 22-year follow-up, 70 men had a fatal or nonfatal stroke. Hyperinsulinemia (highest area under the insulin response curve quintile compared with the combined 4 lower quintiles) was associated with the risk of stroke (age-adjusted hazard ratio, 2.12; 95% CI, 1.28 to 3.49), but not independently of other risk factors (multiple-adjusted hazard ratio, 1.54; 95% CI, 0.90 to 2.62), which was mainly due to the impact of obesity, particularly upper body obesity, with subscapular skinfold thickness used as an index. Of other risk factors, upper body obesity, blood pressure, and smoking were independent predictors of the risk of stroke., Conclusions: Hyperinsulinemia was associated with the risk of stroke in Helsinki policemen during the 22-year follow-up, but not independently of other risk factors, particularly upper body obesity.

Background: The Helsinki Policemen Study is one of the first prospective epidemiological studies demonstrating an association of hyperinsulinemia to the risk of coronary heart disease (CHD). The aim of the present study was to investigate the predictive value of hyperinsulinemia with regard to CHD risk during a 22-year follow-up of the Helsinki Policemen Study population., Methods and Results: The study was based on a cohort of 970 men who were 34 to 64 years of age and free of CHD, other cardiovascular disease, and diabetes. Risk factor measurements at baseline examination included an oral glucose tolerance test (OGTT) with blood glucose and plasma insulin measurements at 0, 1, and 2 hours. Area under the plasma insulin response curve (AUC insulin) during OGTT was used as a composite variable reflecting plasma insulin levels. During the 22-year follow-up, 164 men had a major CHD event (CHD death or nonfatal myocardial infarction). Age-adjusted hazard ratios for a major CHD event comparing men in the highest AUC insulin quintile with those in the combined 4 lower quintiles during 5-, 10-, 15-, and 22-year follow-up periods were 3.29 (95% CI, 1.56 to 6.91), 2.72 (95% CI, 1.67 to 4.42), 2.14 (95% CI, 1.43 to 3.21), and 1.61 (95% CI, 1.14 to 2.27), respectively. Further adjustment for other risk factors attenuated these hazard ratios to 2.36 (95% CI, 1.00 to 5.57), 2.29 (95% CI, 1.31 to 4.02), 1.76 (95% CI, 1.09 to 2.82), and 1.32 (95% CI, 0.89 to 1.97), respectively., Conclusions: Hyperinsulinemia predicted CHD risk in Helsinki policemen over the 22-year follow-up, and to a large extent independently of other CHD risk factors, but its predictive value diminished with lengthening follow-up time.

We performed a subgroup analysis of the first European Stroke Prevention Study including 1,306 patients recruited in a single center, Kuopio, Finland, to investigate whether or not antiplatelet therapy is effective in the secondary prevention of stroke in hypertensive patients with transient ischemic attack (TIA) or stroke. The patients were treated with aspirin, 990 mg/day, plus dipyridamole, 225 mg/day, or placebo for 2 years. The patients with high systolic blood pressure (> or = 140 mm Hg; n = 1.105) or high diastolic blood pressure (> or = 85 mm Hg; n = 1,120) at entry, were classified into subgroups by blood pressure level. The effect of treatment was statistically significant in all subgroups with high systolic (end-point reduction, 55.2-68.2%) and diastolic blood pressure (end-point reduction, 47.3-82.1%). Risk reduction was, however, greatest in patients with the highest diastolic blood pressure. One possible explanation is that platelets are more activated in these patients, and this can be effectively prevented by antiplatelet therapy. Further studies are needed to confirm this hypothesis.

Background and Purpose: Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at increased risk for stroke. Hyperuricemia is a common finding in NIDDM, but its significance as an independent risk factor for cardiovascular disease has remained uncertain. Therefore, we investigated serum urate as a predictor of stroke in NIDDM patients free of clinical nephropathy (ie, with a serum creatinine level of < or = 120 micromol/L)., Methods: In this population-based study, cardiovascular risk factors were determined in 1017 patients (551 men and 466 women) with NIDDM, aged 45 to 64 years at baseline. The patients were followed up for 7 years with respect to stroke events., Results: During the follow-up period, 31 NIDDM patients (12 men [2.2%] and 19 women [4.1%]) died from stroke and 114 NIDDM patients (55 men [10.0%] and 59 women [12.7%]) had a fatal or nonfatal stroke. The incidence of stroke increased significantly by quartiles of serum uric acid levels (P<.001). High uric acid level (above the median value of > 295 micromol/L) was significantly associated with the risk of fatal and nonfatal stroke by Cox regression analysis (hazard ratio, 1.93 [1.30 to 2.86]; P=.001). This association remained statistically significant even after adjustment for all cardiovascular risk factors (hazard ratio, 1.91 [1.24 to 2.94]; P=.003)., Conclusions: Our results indicate that hyperuricemia is a strong predictor of stroke events in middle-aged patients with NIDDM independently of other cardiovascular risk factors.

A preponderance of small, dense LDL has been suggested to be more atherogenic than larger, more buoyant LDL. Although several studies have suggested associations of small, dense LDL with hyperinsulinemia, few data are available on the relation of small, dense LDL to insulin resistance. We examined the association of LDL particle size determined by gradient gel electrophoresis with the rates of whole-body glucose uptake (WBGU) as determined by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 87 Finnish normoglycemic men. LDL size was significantly positively correlated with the rates of WBGU (overall, r = .31, P < .01; oxidative, r = .23, P < .05; and nonoxidative, r = .31, P < .01). Rates of WBGU were also significantly lower in subjects with small LDL particles (< or = 26.0 nm) compared with those in subjects with larger LDL particles (> 26.0 nm). This relation was not explained by obesity. Serum triglyceride concentrations were found to significantly affect the relationship of LDL particle size to WBGU. Specifically, LDL size was correlated with the rates of WBGU in men with mildly elevated triglyceride levels but not in men with low triglyceride levels. Serum VLDL triglyceride concentration was a substantially stronger determinant of LDL size than were the rates of WBGU. WBGU was not significantly related to LDL size when adjusted for triglycerides. We conclude that a preponderance of small, dense LDL particles is associated with insulin resistance and that serum triglyceride concentration modifies this relationship.

Familial combined hyperlipidemia (FCHL) is associated with variable expression of dyslipidemias and insulin resistance. In nondiabetic Pima Indians an A to G substitution in codon 54 of the fatty acid binding protein 2 (FABP2) gene has been shown to be associated with insulin resistance. We screened the entire coding region of this gene by single-strand conformation polymorphism analysis in 24 probands (17 men and 7 women; age, 63.0 +/- 7.4 years [mean +/- SD]; body mass index [BMI], 27.7 +/- 4.2 kg/m2) who had FCHL and in 40 healthy men from a random population sample of 82 men (age, 54.0 +/- 5.0 years; BMI, 26.3 +/- 3.2 kg/m2). Insulin resistance was assessed with the euglycemic clamp in 58 subjects from FCHL families (14 probands with FCHL and 44 first-degree relatives of probands; 38 men and 20 women; age, 51.5 +/- 12.6 years; BMI, 25.5 +/- 3.9 kg/m2). We found three nucleotide substitution in the FABP2 gene: GCT to ACT (Ala-->Thr) in codon 54, GTA to GTG in codon 118, and GCGCA to GCACA in the 3'-noncoding region. Frequencies of these variants did not differ between the patients and control subjects. The Ala to Thr substitution in codon 54 was associated with a high lipid oxidation rate (P = .011 after adjustment for sex and family relationship), high HDL triglycerides (P = .042), and high LDL triglycerides (P = .013) but not with insulin resistance in subjects from FCHL families. The FABP2 gene is unlikely to be a major gene for FCHL, but it might affect lipid metabolism in subjects with FCHL.

We evaluated the effect of a single dose of a cholinesterase inhibitor, tetrahydroaminoacridine (THA; 25 and 50 mg, orally), on attention in patients with Alzheimer's disease (AD). THA 50 mg improved performance in attentional measures (Trail Making Test, Big/Little Circle, Simple and Choice Reaction Time) in nine of 28 patients with AD. We analysed retention of 99mTc-labelled ethylene dicysteinate (ECD) in the cortical areas using single photon emission computed tomography. Those patients who benefited from THA treatment had bilaterally higher frontal and prefrontal ECD retention values. We suggest that THA may improve attention in patients with AD, but a severe frontal dysfunction may block the therapeutic effect of THA.

We studied cognitive function in normoglycaemic elderly subjects at different risk levels for developing non-insulin-dependent diabetes mellitus (NIDDM) and in patients with NIDDM. Risk for NIDDM was considered increased if both 2 h glucose and insulin values on oral glucose tolerance testing were higher than the median in normoglycaemic subjects, and low if the respective values were lower than the median. The increased risk group showed impairment on tests of immediate and delayed memory, attention, visuomotor speed and verbal fluency. Moreover, the increased risk group did not differ from patients with NIDDM on any cognitive tests. Our results suggest that increased risk for NIDDM is associated with widely affected cognitive function in the normoglycaemic elderly, highlighting the importance of healthy living habits.

We compared auditory event-related potentials (ERPs) and neuropsychological test scores in nine patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine control subjects. The measures of automatic stimulus processing, habituation of auditory N100 and mismatch negativity (MMN) were impaired in patients. No differences were observed in the N2b and P3 components, which presumably reflect conscious cognitive analysis of the stimuli. A trend towards impaired performance in the Digit Span backward was found in diabetic subjects, but in the tests of secondary or long-term memory the groups were comparable. Patients with NIDDM may have defects in arousal and in the automatic ability to redirect attention, which can affect their cognitive performance.

Background and Purpose: Increased urinary albumin and protein excretion is associated with cardiovascular disease mortality independent of other cardiovascular risk factors in subjects with non-insulin-dependent diabetes mellitus (NIDDM). We assessed the relationship between the different degrees of proteinuria at baseline and the incidence of stroke, as well as other atherosclerotic vascular disease events, in a prospective study of nondiabetic and NIDDM subjects., Methods: Our study was based on the 7-year follow-up of cohorts of nondiabetic (n = 1375) and NIDDM (n = 1056) subjects in Finland. The urinary protein concentration at baseline was stratified into three categories: no proteinuria (< 150 mg/L), borderline (150 to 300 mg/L), and clinical proteinuria (> 300 mg/L)., Results: The association between the different degrees of proteinuria and the atherosclerotic vascular events was similar in nondiabetic and NIDDM subjects. Cardiovascular disease mortality was higher both in nondiabetic and NIDDM subjects with clinical proteinuria than in those without proteinuria. The incidence of stroke was 1.6% in nondiabetic subjects without proteinuria, 3.2% in subjects with borderline proteinuria, and 8.5% in subjects with clinical proteinuria (P < .001 for trend). In NIDDM patients, the corresponding rates were 7.2%, 11.1%, and 23.0%, respectively (P < .001 for trend). The association between clinical proteinuria and the incidence of stroke remained significant both in nondiabetic and in NIDDM subjects after adjustment for other cardiovascular risk factors. Clinical proteinuria was also associated with the incidence of coronary heart disease events and that of lower-extremity amputation. NIDDM independently increased the risk of atherosclerotic vascular disease events regardless of the proteinuria status., Conclusions: Clinical proteinuria significantly predicted stroke and other atherosclerotic vascular disease events independent of other cardiovascular risk factors. This finding is compatible with the view that increased urinary protein excretion rate may be associated with widespread vascular damage.

Medial artery calcification (MAC) is a nonobstructive condition leading to reduced arterial compliance that is commonly considered as a nonsignificant finding. The aim of our study was to investigate the predictive value of MAC in relation to 7-year cardiovascular mortality, coronary heart disease (CHD) events, stroke, and lower extremity amputation in 1059 patients (581 men and 478 women) with non-insulin-dependent diabetes mellitus (NIDDM). At baseline radiologically detectable MAC in femoral arteries was found in 439 patients (41.5%) and intimal-type calcification in 310 diabetic patients (29.3%). The mean fasting plasma glucose at baseline was somewhat higher in women and the duration of diabetes somewhat longer in patients with MAC than in those without, but otherwise the presence of MAC was unrelated to conventional cardiovascular risk factors. During the follow-up 305 diabetic patients died: 208 from cardiovascular disease, 158 from CHD, and 34 from stroke. Furthermore, 58 NIDDM patients underwent their first lower extremity amputation. MAC was a strong independent predictor of total (risk factor-adjusted odds ratio and 95% confidence interval: 1.6; 1.2, 2.2), cardiovascular (1.6; 1.1, 2.2), and CHD (1.5; 1.0, 2.2) mortality, and it was also a significant predictor of future CHD events (fatal or nonfatal myocardial infarction), stroke, and amputation. This relationship was observed regardless of glycemic control and known duration of NIDDM. MAC is a strong marker of future cardiovascular events in NIDDM unrelated to cardiovascular risk factors, supporting the hypothesis that reduced arterial elasticity could lead to clinical manifestations of diabetic macroangiopathy.

Insulin resistance and hyperinsulinaemia often occur with many cardiovascular risk factors. Whether hyperinsulinaemia and insulin resistance are risk factors for coronary heart disease is still a matter of debate. The information from prospective population studies, in which the relationship between hyperinsulinaemia and coronary heart disease has been investigated, is summarized. The possibility that hyperinsulinaemia and insulin resistance increase the risk for coronary heart disease will be approached from two angles. Evidence is presented of how hyperinsulinaemia and insulin resistance increase the risk for coronary heart disease indirectly through their effects on cardiovascular risk factors. Finally, evidence of how hyperinsulinaemia and insulin resistance could directly promote atherosclerosis is reviewed.

We analyzed hippocampal volumes and T2 relaxation times by MRI from 78 control subjects, 24 patients with temporal lobe epilepsy, and 55 patients with Alzheimer's disease (AD). In the epilepsy group, the hippocampal volumes were 27% smaller than in control subjects (p < 0.001). The T2 relaxation times were prolonged (8 to 20 ms compared with control subjects) in the head, body, and tail portions of the hippocampus on the focal side (p < 0.01) and also on the contralateral side (p < 0.05) compared with control subjects. In the epilepsy group, the prolongation of T2 relaxation time correlated inversely with the hippocampal volume (p < 0.05). In the AD group, the hippocampal volumes were 35% smaller than in control subjects (p < 0.01). The T2 relaxation times were slightly prolonged (5 to 6 ms) in the head and tail portions of the right hippocampus (p < 0.01), but the T2 relaxation times did not correlate with the hippocampal volumes. These data show that the degree of prolongation of T2 relaxation time is associated with severity of hippocampal atrophy in temporal lobe epilepsy but not in AD.