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Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process., (Copyright © 2016, American Association for the Advancement of Science.)

In postmenopausal coronary artery disease (CAD) women, serum plant sterols are elevated. Thus, we investigated further whether serum plant sterols reflect absolute cholesterol metabolism in CAD as in other populations and whether the ABCG5 and ABCG8 genes, associated with plant sterol metabolism, were related to the risk of CAD. In free-living postmenopausal women with (n = 47) and without (n = 62) CAD, serum noncholesterol sterols including plant sterols were analyzed with gas-liquid chromatography, cholesterol absorption with peroral isotopes, absolute cholesterol synthesis with sterol balance technique, and bile acid synthesis with quantitating fecal bile acids. In CAD women, serum plant sterol ratios to cholesterol were 21% to 26% (P < .05) higher than in controls despite similar cholesterol absorption efficiency. Absolute cholesterol and bile acid synthesis were reduced. Only in controls were serum plant sterols related to cholesterol absorption (eg, sitosterol; in controls: r = 0.533, P < .001; in CAD: r = 0.296, P = not significant). However, even in CAD women, serum lathosterol (relative synthesis marker) and lathosterol-cholestanol (relative synthesis-absorption marker) were related to absolute synthesis and absorption percentage (P range from .05 to <.001) similarly to controls. Frequencies of the common polymorphisms of ABCG5 and ABCG8 genes did not differ between coronary and control women. In conclusion, plant sterol metabolism is disturbed in CAD women; so serum plant sterols only tended to reflect absolute cholesterol absorption. Other relative markers of cholesterol metabolism were related to the absolute ones in both groups. ABCG5 and ABCG8 genes were not associated with the risk of CAD.

Objective: Low serum zinc level may predispose nondiabetic subjects to cardiovascular diseases. Our aim was to investigate whether serum zinc level predicts coronary heart disease (CHD) events in subjects with type 2 diabetes, Research Design and Methods: The original study population consisted of 1,059 patients with type 2 diabetes, aged 45-64 years. Mean duration of diabetes was 8 years. Serum zinc values were available from 1,050 subjects. CHD mortality and the incidence of nonfatal myocardial infarction (MI) were assessed in a 7-year follow-up., Results: During the follow-up, 156 patients died from CHD and 254 patients had a fatal or nonfatal MI. Patients with serum zinc concentration < or = 14.1 micromol/l at baseline had a higher risk for death from CHD than patients with serum zinc level > 14.1 micromol/l (20.8 and 12.8%, respectively; P = 0.001) The risks for fatal or nonfatal MI were 30.5 and 22.0%, respectively (P = 0.005). In Cox regression analyses, low serum zinc concentration was significantly associated with CHD mortality (relative risk [RR] 1.7, P = 0.002) and all CHD events (RR 1.37, P = 0.030), even after adjustment for confounding variables., Conclusions: In this large cohort of type 2 diabetic patients, low serum zinc level was an independent risk factor for CHD events.

Objective: To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences., Research Design and Methods: Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality., Results: Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy., Conclusions: Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.

Objective: To investigate in a follow-up study whether high-sensitivity C-reactive protein (hs-CRP) predicts coronary heart disease (CHD) events in subjects with type 2 diabetes., Research Design and Methods: The original study population consisted of 1,059 patients with type 2 diabetes (age 45-64 years). Mean duration of diabetes was 8 years. CRP values were available from 1,045 subjects, of whom 878 were free of myocardial infarction (MI) at baseline. CHD mortality and the incidence of nonfatal MI were assessed in a 7-year follow-up., Results: Altogether, 157 patients died from CHD and 254 had a nonfatal or fatal CHD event. Patients with hs-CRP >3 mg/l had a higher risk for CHD death than patients with hs-CRP < or =3 mg/l (19.8 and 12.9%, respectively, P = 0.004). In Cox regression analysis, patients with high hs-CRP had a relative risk of 1.72 for CHD death even after the adjustment for confounding factors (P = 0.002). Among subjects who were free from MI at baseline, those with a high hs-CRP level had relative risks of 1.83 (P = 0.003) and 1.84 (P = 0.004) for CHD death in univariate and multivariate analyses, respectively., Conclusions: In this large cohort of type 2 diabetic patients, hs-CRP was an independent risk factor for CHD deaths.

Autoantibodies against oxidized low-density lipoprotein (oxLDL) predict the progression of atherosclerosis. Several studies have shown that oxLDL is present in atherosclerotic lesions and that several factors present in active atherosclerotic plaques can oxidatively modify LDL. Oxidation of LDL induces production of autoantibodies against oxLDL (oxLDLab) that can be measured using an EIA test. Our aim was to see whether oxLDLab are associated with severe chest pain attacks in coronary heart disease (CHD) patients. Patients having two- or three-vessel CHD, as assessed by coronary angiography, and their siblings were recruited into the study (n = 568, mean age 55.8 years, range 29.3-83.2 years). Nondiabetic patients having a history of severe chest pain attacks had significantly higher oxLDLab levels (0.611 +/- 0.56) than those who did not have a history of severe chest pain attacks (0.487 +/- 0.40) (p = 0.027), even though age, cholesterol level, body mass index, and blood pressure were similar in both groups. However, no difference was found in oxLDLab levels in diabetic patients with or without a history of severe chest pain attacks. Increased levels of oxLDL autoantibodies are associated with severe chest pain attacks in nondiabetic patients with CHD.

Objective: The purpose of this study was to investigate the hypothesis that coronary heart disease (CHD) mortality in diabetic subjects without prior evidence of CHD is equal to that in nondiabetic subjects with prior myocardial infarction or any prior evidence of CHD., Research Design and Methods: During an 18-year follow-up total, cardiovascular disease (CVD) and CHD deaths were registered in a Finnish population-based study of 1,373 nondiabetic and 1,059 diabetic subjects., Results: Adjusted multivariate Cox hazard models indicated that diabetic subjects without prior myocardial infarction, compared with nondiabetic subjects with prior myocardial infarction, had a hazard ratio (HR) of 0.9 (95% CI 0.6-1.5) for the risk of CHD death. The corresponding HR was 0.9 (0.5-1.4) in men and 1.9 (0.6 -6.1) in women. Diabetic subjects without any prior evidence of CHD (myocardial infarction or ischemic electrocardiogram [ECG] changes or angina pectoris), compared with nondiabetic subjects with prior evidence of CHD, had an HR of 1.9 (1.4-2.6) for CHD death (men 1.5 [1.0-2.2]; women 3.5 [1.8-6.8]). The results for CVD and total mortality were quite similar to those for CHD mortality., Conclusions: Diabetes without prior myocardial infarction and prior myocardial infarction without diabetes indicate similar risk for CHD death in men and women. However, diabetes without any prior evidence of CHD (myocardial infarction or angina pectoris or ischemic ECG changes) indicates a higher risk than prior evidence of CHD in nondiabetic subjects, especially in women.

Background: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes., Methods: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993., Findings: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups., Interpretation: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

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.

Objective: To explain the stronger effect of type 2 diabetes on the risk of coronary heart disease (CHD) in women compared with men., Research Design and Methods: The study population consisted of 1,296 nondiabetic subjects and 835 type 2 diabetic subjects aged 45-64 years without cardiovascular disease. The end points were CHD death and a major CHD event (CHD death or nonfatal myocardial infarction). The follow-up time was 13 years., Results: Major CHD event rate per 1,000 person-years was 11.6 in nondiabetic men, 1.8 in nondiabetic women, 36.3 in diabetic men, and 31.6 in diabetic women. The diabetes-related hazard ratio for a major CHD event from the Cox model, adjusted for age and area of residence, was 2.9 (95% CI 2.2-3.9) in men and 14.4 (8.4-24.5) in women, and after further adjustment for cardiovascular risk factors, 2.8 (2.0-3.7) and 9.5 (5.5-16.9), respectively. The burden of conventional risk factors in the presence of diabetes was greater in women than in men at baseline. Prospectively, elevated blood pressure, low HDL cholesterol, and high triglycerides contributed to diabetes-related CHD risk more in women than in men. However, after adjusting for conventional risk factors, a substantial proportion of diabetes-related CHD risk remained unexplained in both genders., Conclusions: The stronger effect of type 2 diabetes on the risk of CHD in women compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in diabetic women.

Background: High plasma homocysteine level has been associated with increased risk for coronary heart disease (CHD) events in nondiabetic individuals, especially in those with previously diagnosed CHD. In persons with type 2 diabetes mellitus, the association between homocysteine level and cardiovascular disease may be stronger than that in nondiabetic individuals, but no large prospective studies have examined the relationship between homocysteine level and CHD mortality in persons with type 2 diabetes., Objective: To investigate whether moderately elevated plasma homocysteine levels are independently related to increased incidence of fatal and nonfatal CHD events in persons with type 2 diabetes., Design: Prospective study., Setting: Finnish sample of patients with type 2 diabetes., Patients: 462 men and 368 women who were 45 to 64 years of age at baseline., Measurements: Coronary heart disease mortality and incidence of nonfatal myocardial infarction during the 7-year follow-up., Results: Participants with plasma homocysteine levels of 15 micromol/L or more at baseline had a higher risk for CHD death than those with plasma homocysteine levels less than 15 micromol/L (26.1% and 13.5%, respectively; P = 0.005). The risks for all CHD events were 36.2% and 22.6%, respectively (P = 0.011). In Cox regression analyses, elevated plasma homocysteine level was significantly associated with CHD mortality (P < 0.001) and all CHD events (P = 0.002) even after adjustment for confounding variables, including creatinine clearance. In participants without myocardial infarction at baseline, moderate hyperhomocysteinemia was also associated with CHD mortality and all CHD events in univariate (P < 0.001 and P = 0.006, respectively) and multivariate Cox regression analyses (P < 0.001 and P = 0.004, respectively)., Conclusions: In this large cohort of patients with type 2 diabetes, plasma homocysteine level was a strong and independent risk factor for CHD events.

Several genomewide screens have been performed to identify novel loci predisposing to unfavorable serum lipid levels and coronary heart disease (CHD). We hypothesized that the accumulating data of these screens in different study populations could be combined to verify which of the identified loci truly harbor susceptibility genes. The power of this strategy has recently been demonstrated with other complex diseases, such as inflammatory bowel disease and asthma. We assessed the largely unknown genetic background of CHD by investigating the most common dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL), affecting 1%-2% of Western populations and 10%-20% of families with premature CHD. To be able to perform a combined data analysis, we unified the diagnostic criteria for FCHL and its component traits and combined the data from two genomewide scans performed in two populations, the Finns and the Dutch. As a result of our pooled data analysis, we identified three chromosomal regions, on chromosomes 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a LOD score >2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein cholesterol (HDL-C) trait. In addition, the previously recognized 1q21 region also obtained additional support in the other study sample, when the triglyceride trait was used. Analysis of the 16q24.1 region resulted in a statistically significant LOD score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families.

Objective: To investigate whether quantity or quality of dietary fat predicts coronary heart disease (CHD) events in middle-aged type 2 diabetic subjects., Research Design and Methods: The dietary habits of 366 type 2 diabetic men and 295 women, aged 45-64 years and free from CHD, were assessed with a 53-item food frequency questionnaire. They were followed up for 7 years., Results: Men in the highest tertile of the polyunsaturated/saturated fat (P/S) ratio (>0.28) had a significantly lower risk for CHD death than men in the two lowest tertiles (5.0 vs. 14.2%, P = 0.009). The risk for all CHD events was 14.2 vs. 23.2%, respectively (P = 0.044). P/S ratio did not predict CHD events in women. In Cox multiple regression analyses taking into account other cardiovascular risk factors, the highest P/S ratio tertile was associated with the lowest rate of CHD death in men (P = 0.048)., Conclusions: Low P/S ratio in men predicted future CHD events in type 2 diabetic subjects independently of conventional CHD risk factors.

Background: There has been no previous study to determine the severity and extent of coronary artery disease (CAD) in subjects with no diagnosis or symptoms of CAD at the time of the angiography., Methods: Fifty-three subjects, who were siblings of patients with early onset CAD, underwent coronary angiography. Indices to describe per-patient characteristics of CAD were calculated, based on computer-aided quantitative coronary angiography. Clinical and laboratory characteristics were correlated to the angiographic parameters., Results: Serum total homocysteine (rho = 0.29, P < 0.05) and creatinine (rho = 0.47, P = 0.001) levels were related to the global atheroma burden index. The median of the atheroma burden index was two times higher in the top homocysteine quartile compared to the lowest quartile. The overall atheroma burden index correlated significantly with the fasting blood glucose level in all subjects. Diabetes, especially when albuminuria was present, was a powerful risk factor. In a multivariate analysis, only age and sex were independent predictors of atheroma burden., Conclusions: Serum homocysteine and creatinine concentrations, and diabetes with albuminuria were found to be markers of the severity and extent of CAD in subjects of high-risk families without symptoms of CAD.

Background and Aim: It has been suggested that the threonine (Thr) 54 allele of the intestinal fatty acid binding protein 2 (FABP2) gene is associated with insulin resistance and affects the fatty acid composition of serum lipids. Our aim was to investigate the frequency of the alanine (Ala) 54Thr polymorphism of the FABP2 gene in patients with coronary heart disease (CHD), and the association between the polymorphism and the markers of metabolic syndrome, serum lipid levels and the fatty acid profile of serum lipids., Methods and Results: A total of 414 CHD patients (mean age 61 years, range 33-74) participated in the cross-sectional EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events) Study. Markers of metabolic syndrome included fasting plasma glucose concentration, serum high-density lipoprotein cholesterol and triglycerides (TG), waist circumference, the waist/hip ratio, body mass index (BMI) and blood pressure (BP). The frequency of the Thr54 allele was similar in the CHD patients (27.2%) and control subjects from two independent studies (27.8% and 28.7%). There were no significant differences in plasma glucose, serum lipids, BP, BMI, waist circumference or waist/hip ratio among the genotypes. Genotype frequency was not associated with the prevalence of diabetes or metabolic syndrome, but metabolic syndrome (as defined by National Cholesterol Education Program criteria) tended to be more frequent in subjects with the Thr/Thr genotype (p = 0.095). There were no differences in the fatty acid profiles of serum cholesteryl esters, TG or phospholipids among the genotypes., Conclusions: The Ala54Thr polymorphism of the FABP2 gene is not associated with CHD, markers of the metabolic syndrome, or the fatty acid profile of serum lipids in Finnish CHD patients.

Leucine 7 (Leu7) to proline 7 (Pro7) substitution in the neuropeptide Y (NPY) gene has been associated with higher serum total and low-density lipoprotein (LDL) cholesterol levels, particularly in obese subjects. We investigated the frequency of the Pro7 allele and the association of the polymorphism with serum lipid levels in patients with coronary heart disease (CHD). A total of 414 CHD patients (mean age 61 years, range 33-74) participated in the cross-sectional EUROASPIRE study. Of the subjects 39% used lipid-lowering drugs. The frequency of the Pro7 allele in CHD patients (0.082) did not differ from that in control subjects (0.071). The mean (+/-SD) serum total cholesterol concentration was higher in women with the Pro7 allele (7.57 +/- 0.57 mmol/L, n = 8) than in women with the Leu7Leu genotype (6.69 +/- 1.01 mmol/L, n = 69, P = 0.019), when subjects using lipid-lowering medication were excluded. In contrast, serum total cholesterol concentration did not significantly differ between the genotypes in men. The Leu7Pro polymorphism was not associated with serum LDL, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations. In conclusion, the Pro7 allele in the NPY gene was associated with higher serum total cholesterol concentration only in women with CHD who did not use lipid-lowering drugs.

The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.

Objective: To investigate whether cardiovascular risk factors cluster with hyperinsulinemia in elderly type 2 diabetic subjects and, if so, whether this clustering predicts coronary heart disease (CHD) events during a 7-year follow-up., Research Design and Methods: Clustering of cardiovascular risk factors was analyzed by factor analysis. Cox regression models were used to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) during a 7-year follow-up in 229 type 2 diabetic subjects aged 65-74 years., Results: There were 70 CHD events (21 in men and 49 in women) during the follow-up period. In diabetic men, components of the insulin resistance syndrome (IRS) loaded on Factor 1 (the insulin resistance factor), which reflected high fasting insulin, obesity (high BMI), central obesity (high waist-to-hip ratio), high total triglycerides, and a short duration of diabetes. Only this IRS factor predicted CHD events in multivariate Cox regression analysis (hazard ratio [HR] 1.71, 95% CI 1.08-2.71, P = 0.022). In diabetic women, components of IRS loaded on two factors, none of which predicted CHD events. In women, only Factor 4, characterized by advanced age, left ventricular hypertrophy on electrocardiogram, high alcohol consumption, high systolic blood pressure, and albuminuria, predicted CHD events in multivariate Cox regression analysis (1.34, 1.03-1.74, P = 0.03)., Conclusions: IRS is a risk factor for CHD in elderly type 2 diabetic men.

Polymorphisms of the angiotensin-converting enzyme (ACE) (insertion/deletion (I/D) in intron 16) and of the plasminogen activator inhibitor-1 (PAI-1) (promoter 4G/5G) genes have been linked with coronary heart disease (CHD) and/or myocardial infarction (MI). We studied the association of polymorphisms in these genes with CHD with linkage and association analyses in 118 families with premature and severe CHD and in 110 healthy controls. In linkage analysis there was no evidence for a linkage of the ACE or PAI-1 loci with CHD. However, in quantitative linkage analysis the ACE locus was linked with fasting glucose (P=0. 047) and fasting free fatty acid levels (P=0.029). In association analysis the ACE genotype frequencies of probands with CHD did not differ from those of healthy controls. Normoglycemic probands with MI and with the ACE polymorphism DD genotype had characteristics of the insulin resistance syndrome. They had higher levels of 1-h glucose (P=0.008) and 2-h free fatty acids (P=0.011) in an oral glucose tolerance test and higher levels of total (P=0.005) and very-low-density lipoprotein triglycerides (P=0.006) than probands with the ID or the II genotypes. The PAI-1 gene polymorphism was not associated with any of the variables of glucose or lipid metabolism. In conclusion, the ACE and PAI-1 gene polymorphisms are not linked with early-onset CHD. However, the ACE gene polymorphism is associated with features of the insulin resistance syndrome.

Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. To assess the genetic background of CHD, we performed a genomewide linkage scan in two study samples from the genetically isolated population of Finland. An initial study sample consisted of family material from the northeastern part of Finland, settled by a small number of founders approximately 300 years ago. A second study sample originated from the southwestern region of Finland, settled approximately 2,000 years ago. Families were ascertained through probands exhibiting premature CHD, defined as >50% stenosis of at least two coronary arteries at a young age, as verified by coronary angiography. Both study samples and the pooled data set provided evidence for linkage in two chromosomal regions. A region on chromosome 2q21.1-22 yielded two-point LOD scores of 3.2, 1.9, and 3.7, in the affected sib-pair (ASP) analyses of the northeastern, southwestern, and pooled study samples. The corresponding multipoint maximum-likelihood scores (MLSs) for these three study samples were 2.4, 1.3, and 3.0. In addition, a region on chromosome Xq23-26 resulted in two-point LOD scores of 1.9, 3.5, and 2.9 and in multipoint MLSs of 3.4, 3.1, and 2.5, respectively. In conclusion, this study identifies two loci likely to contribute to premature CHD: one on chromosome 2q21.1-22 and another on chromosome Xq23-26.

Objective: To study the prevalence of depression at least 6 months after various coronary heart disease (CHD) events (bypass grafting, coronary angioplasty, myocardial infarction, myocardial ischaemia without infarction) and the associations between depression and clinical variables., Design: In the course of the study 414 (284 males, 130 females) patients younger than 71 years (mean age for men 60.9 years and for women 63.6 years) were interviewed and examined. Smoking habits, body mass index, lipid levels and diabetic status were recorded. The New York Heart Association (NYHA) class was assessed. Depression was screened using a self-rated depression scale., Results: In the four diagnostic categories, one-sixth of the patients (14-19%) suffered from depression. Depression was associated with smoking (OR 1.7, 95% CI 1.2; 2.4) and poor NYHA class (OR 1.9, 95% CI 1.4; 2.6)., Conclusion: Depression is common after CHD events, and is associated with smoking and poor NYHA class. The identification and treatment of depression should be one of the elements in the rehabilitation of cardiac patients.

Objective: Elevated HDL cholesterol and its principal carrier protein apolipoprotein a1 [apo(a1)] are associated with reduced risk of coronary heart disease (CHD). No studies are available on the impact of the -75-bp and/or +83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes., Research Design and Methods: We determined the prevalence of the: -75-bp and +83-bp polymorphisms of the apo(a1) gene by restriction fragment length polymorphism analysis among 308 unrelated nondiabetic subjects with CHD and among 251 unrelated patients with type 2 diabetes with CHD and in randomly selected 82 healthy men (CHD-)., Results: The rare M1- and M2- allele frequencies of the apo(a1) gene were 23 and 1.8%, respectively, among control subjects; 20 and 1.5%, respectively, among nondiabetic subjects with CHD; and 22 and 2.6%, respectively, among patients with type 2 diabetes and CHD (NS). Nonsmoking nondiabetic subjects with CHD having the M2+- genotype had higher HDL cholesterol (1.48 +/- 0.19 vs. 1.23 +/- 0.02 mmol/l, P < 0.01) and apo(a1) (1.43 +/- 0.10 vs. 1.36 +/- 0.02 g/l, P < 0.05) levels than subjects with the M2++ genotype, even after adjustment for confounding factors. This association was not found among patients with type 2 diabetes and CHD., Conclusions: We conclude that the +83-bp polymorphism of the apo(a1) gene is associated with elevated HDL cholesterol and apo(a1) levels in Finnish nondiabetic subjects but not in patients with type 2 diabetes.

Aims/hypothesis: Information on the association of hyperinsulinaemia with coronary heart disease (CHD) in patients with Type II (non-insulin-dependent) diabetes is limited and controversial. Therefore, we carried out a prospective study to examine the predictive value of fasting plasma insulin and "hyperinsulinaemia cluster" with regard to the risk of CHD mortality., Methods: At baseline risk factors for CHD were determined in 902 patients aged 45 to 64 years with Type II diabetes not treated by insulin (499 men and 403 women). These patients were followed up to 7 years for CHD mortality., Results: Coronary heart disease mortality (16.2% in men, 9.2% in women) increased significantly in men with increasing plasma insulin tertiles (p = 0.006) and in both sexes combined (p = 0.010) but not in women (p = 0.090). The predictive value of hyperinsulinaemia with regard to death from CHD was independent of conventional cardiovascular risk factors but not of risk factors clustering with hyperinsulinaemia. By applying factor analysis and principal component analysis we showed that "hyperinsulinaemia cluster" (a factor having high positive loadings for body mass index, triglycerides and insulin; and a high negative loading for high-density lipoprotein cholesterol) was predictive of death from CHD in patients with Type II diabetes (hazard ratio with 95% confidence intervals 1.43 (1.18, 1.73), p < 0.001)., Conclusion/interpretation: Our results support the notion that cardiovascular risk factors clustering with endogenous hyperinsulinaemia increase the risk of death from CHD in patients with Type II diabetes not treated with insulin.

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.

The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.

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.

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.

Hyperinsulinemia has been shown to predict coronary heart disease (CHD) events in both nondiabetic subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, defects in genes that regulate insulin action could be responsible for an increased risk of CHD. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene has been linked with abdominal obesity, insulin resistance, and early-onset NIDDM. Therefore, we screened for this polymorphism among 185 unrelated nondiabetic subjects (101 men and 84 women; age, 56+/-1 years [mean +/- SEM]; body mass index [BMI], 27.8+/-0.3 kg/m2) with angiographically confirmed CHD (stenosis > 50% in > or = two coronary arteries), among 119 unrelated patients with NIDDM (90 men and 29 women; age, 62+/-1 years; BMI, 28.7+/-0.4 kg/m2; 95 had CHD by the same criteria and 24 had definite myocardial infarction [MI]), and among 82 healthy men (age, 54+/-1 years; BMI, 26.3+/-0.4 kg/m2) from our previous study. The frequency of the Trp64Arg allele of the beta3-adrenergic receptor gene was similar in nondiabetic patients with CHD (8%), NIDDM patients with CHD (7%), and nondiabetic subjects without CHD (7%). No association was found between cardiovascular risk factors and the codon 64 polymorphism of the beta3-adrenergic receptor gene in patients with CHD. Similarly, this polymorphism was not significantly related to insulin resistance in nondiabetic and NIDDM subjects with CHD evaluated by the euglycemic clamp technique. These results indicate that the Trp64Arg allele of the beta3-adrenergic receptor gene does not contribute to the risk of CHD in nondiabetic subjects and NIDDM patients.

Of the threats to health and life that beset the person with diabetes, cardiovascular disease (CVD), particularly coronary heart disease (CHD) but also cerebrovascular and peripheral vascular disease, represent the heaviest burden. The relative risk for CVD is very high for Type 1 diabetes, but the absolute risk, in terms of numbers, is much higher for Type 2. In all societies, diabetes increases cardiovascular risk twofold or more, compared with the local non-diabetic population. Some of the evidence for this diabetes-related increase in cardiovascular risk is reviewed and its relationship to recognised cardiovascular risk factors considered. The explanation of the enhanced susceptibility to atherosclerotic disease in diabetes remains a matter of contention. How much can be explained by greater prevalence in diabetes of such risk factors as hypertension and dyslipidaemia? To what extent is the impact of a given level of risk factor magnified by a co-existing diabetic state? Is the increased cardiovascular morbidity and mortality secondary to risk factors specifically related to the diabetic state itself? Does the explanation lie in altered coagulability due to changes in platelet activation and aggregability, fibrinogen levels, Factor VII, von Willebrand factor or PAI-1, in the concentration or composition of plasma lipoproteins, in defective endothelial cell function or other metabolic abnormalities of the arterial wall? To what extent is cardiovascular risk related to the degree of hyperglycaemia, protein glycation, relative hyperinsulinaemia and insulin resistance? Data from recent epidemiological, intervention and laboratory investigations bearing on causation, management and prevention of CVD in diabetes are reviewed. Evidence for the impact of correction of glycaemia, dyslipidaemia and raised arterial pressure is considered and reasons are adduced for a broad and proactive therapeutic approach with early identification and vigorous correction of key risk factors., (Copyright 1999 John Wiley & Sons, Ltd.)

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.

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.

Background: Type 2 (non-insulin-dependent) diabetes is associated with a marked increase in the risk of coronary heart disease. It has been debated whether patients with diabetes who have not had myocardial infarctions should be treated as aggressively for cardiovascular risk factors as patients who have had myocardial infarctions., Methods: To address this issue, we compared the seven-year incidence of myocardial infarction (fatal and nonfatal) among 1373 nondiabetic subjects with the incidence among 1059 diabetic subjects, all from a Finnish population-based study., Results: The seven-year incidence rates of myocardial infarction in nondiabetic subjects with and without prior myocardial infarction at base line were 18.8 percent and 3.5 percent, respectively (P<0.001). The seven-year incidence rates of myocardial infarction in diabetic subjects with and without prior myocardial infarction at base line were 45.0 percent and 20.2 percent, respectively (P<0.001). The hazard ratio for death from coronary heart disease for diabetic subjects without prior myocardial infarction as compared with nondiabetic subjects with prior myocardial infarction was not significantly different from 1.0 (hazard ratio, 1.4; 95 percent confidence interval, 0.7 to 2.6) after adjustment for age and sex, suggesting similar risks of infarction in the two groups. After further adjustment for total cholesterol, hypertension, and smoking, this hazard ratio remained close to 1.0 (hazard ratio, 1.2; 95 percent confidence interval, 0.6 to 2.4)., Conclusions: Our data suggest that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction. These data provide a rationale for treating cardiovascular risk factors in diabetic patients as aggressively as in nondiabetic patients with prior myocardial infarction.

Objective: To investigate the association of variants of the fatty acid-binding protein (FABP) 2 gene with coronary heart disease (CHD) in nondiabetic subjects and in patients with NIDDM., Research Design and Methods: Cross-sectional study included 135 nondiabetic and 79 NIDDM subjects with stenosis (> 50%) in at least two coronary arteries. A group of 81 healthy nondiabetic men without CHD served as a control population. All exons and intron-exon junctions of the FABP2 gene were amplified with the polymerase chain reaction, and variants were screened with the single-strand conformation polymorphism analysis., Results: The allele frequency of an amino acid polymorphism (alanine-->threonine) in codon 54 of exon 2 of the FABP2 gene was 0.26 in nondiabetic subjects with CHD and 0.27 in NIDDM subjects with CHD. Other variants (GTA 118 GTC, GCGCA-->GCACA in the 3'-noncoding region, and the number of ATT repeats in intron 2) also did not associate with CHD., Conclusions: The variants of the FABP2 gene are not likely to contribute to the risk of CHD in Finnish nondiabetic and NIDDM subjects.

Patients with NIDDM 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 the risk for CHD in diabetic patients is still limited. Therefore, we carried out a prospective study on risk factors for CHD, including a large number of NIDDM patients. At baseline, risk factor levels of CHD were determined in 1,059 NIDDM patients (581 men and 478 women), aged from 45 to 64 years. These patients were followed up to 7 years with respect to CHD events. Altogether, 158 NIDDM patients (97 men [16.7%] and 61 women [12.8%]) died of CHD and 256 NIDDM patients (156 men [26.8%] and 100 women [20.9%]) had a serious CHD event (death from CHD or nonfatal myocardial infarction). A previous history of myocardial infarction, low HDL cholesterol level (<1.0 mmol/l), high non-HDL cholesterol (> or =5.2 mmol/l), high total triglyceride level (>2.3 mmol/l), and high fasting plasma glucose (>13.4 mmol/l) were associated with a twofold increase in the risk of CHD mortality or morbidity, independently of other cardiovascular risk factors. High calculated LDL cholesterol level (> or =4.1 mmol/l) was significantly associated with all CHD events. The simultaneous presence of high fasting glucose (>13.4 mmol/l) with low HDL cholesterol, low HDL-to-total cholesterol ratio, or high total triglycerides further increased the risk for CHD events up to threefold. Our 7-year follow-up study provides evidence that dyslipidemia and poor glycemic control predict CHD mortality and morbidity in patients with NIDDM.

Objectives: To study the changes in autonomic nervous function during the 4-year follow-up period in diabetic patients and to investigate factors predicting autonomic nervous dysfunction., Design: A 4-year follow-up study., Setting: At baseline the study subjects without known cardiovascular disease were recruited from a large group of diabetic and nondiabetic subjects selected randomly from a baseline population., Subjects: Middle-aged control subjects (n = 44), patients with insulin-dependent diabetes mellitus (n = 32) and patients with non-insulin-dependent diabetes mellitus (n = 32) were studied at baseline and after the 4-year follow-up., Interventions: Autonomic nervous function tests and exercise test at baseline and after the 4-year follow-up., Results: At the baseline, heart rate variation during deep breathing was significantly lower in patients with insulin-dependent diabetes (13.0 +/- 1.2 beats min-1; P < 0.05) and in patients with non-insulin-dependent diabetes (12.9 +/- 1.5 beats min-1; P < 0.05) than in control subjects (16.6 +/- 1.1 beats min-1). At baseline, autonomic nervous function score was significantly higher indicating disturbed autonomic nervous function in patients with insulin-dependent diabetes (1.74 +/- 0.19; P < 0.01) than in control subjects (1.24 +/- 0.14), but the difference was not significant between control subjects and patients with non-insulin-dependent diabetes (1.47 +/- 0.12). During the follow-up, autonomic nervous function score increased in patients with non-insulin-dependent diabetes to 2.00 +/- 0.21 (P < 0.001, as compared to baseline), but did not change in patients with insulin-dependent diabetes (1.77 +/- 0.18) or control subjects (1.22 +/- 0.12). In both diabetic groups, the deterioration of autonomic nervous function score during the 4-year follow-up was associated with poor glycaemic control at baseline. Clinical manifestation of coronary heart disease was found in three (7%) control subjects, 12 (37%; P < 0.001) patients with insulin-dependent diabetes and 11 (34%; P < 0.01) patients with non-insulin-dependent diabetes mellitus at follow-up examination. Autonomic nervous function was more abnormal in those insulin-dependent diabetic patients with coronary heart disease than those without., Conclusions: During the 4-year follow-up the impairment in autonomic nervous function occurred mainly in patients with noninsulin-dependent diabetes. Poor glycaemic control appears to be an important determinant of the progression of autonomic nervous dysfunction in diabetes.

Lipid and lipoprotein abnormalities in non-insulin-dependent diabetes mellitus (NIDDM) include particularly elevated levels of total and very-low-density lipoprotein (VLDL) triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate. The worsening of glycemic control deteriorates lipid and lipoprotein abnormalities and particularly total and LDL cholesterol levels are often elevated in patients with poor glycemic control. According to prospective population-based studies total cholesterol is a powerful risk factor for coronary heart disease (CHD) in NIDDM patients as in nondiabetic subjects. In contrast, high total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals, but more prospective studies are needed to substantiate this view. Compositional changes in LDL and VLDL particles may further increase the risk for CHD but epidemiologic data are missing to support this notion. Preliminary data from the Scandinavian Simvastatin Survival Study including 202 diabetic patients seem to indicate that diabetic patients benefit from simvastatin treatment equally to nondiabetic subjects.

Objective: Proliferative retinopathy has been shown to be associated with increased all-cause mortality in diabetic patients. We assessed the relationship between the different degrees of retinopathic changes at baseline and serious coronary heart disease (CHD) events (CHD death or nonfatal myocardial infarction) in a prospective population-based study of NIDDM patients., Research Design and Methods: Our study is based on the 7-year follow-up cohort of 1,059 NIDDM patients in east and west Finland. Classification of retinopathic changes was based on clinical examination of fundi, and the findings were classified to three categories according to the status of the worse eye: no retinopathic changes, background retinopathy, and proliferative retinopathy., Results: During the 7-year follow-up, 255 (24%) patients developed serious CHD event. In patients with proliferative retinopathy at baseline, the risk of CHD events during the follow-up was statistically significantly higher compared with patients without retinopathic changes (odds ratio [OR] 2.31, 95% CI 1.21-4.40). The association between proliferative retinopathy and CHD events remained significant when other cardiovascular risk factors were controlled for., Conclusions: Proliferative retinopathy in NIDDM patients was associated with CHD events. Our findings suggest that retinopathy and CHD may have similar pathophysiological backgrounds.

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.

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.

Dyslipidaemia is frequent in non-insulin-dependent diabetes mellitus (NIDDM). Lipid and lipoprotein abnormalities include particularly elevated levels of total and very-low-density lipoprotein (VLDL) triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. The worsening of glycaemic control further deteriorates lipid and lipoprotein abnormalities and furthermore, total and low-density lipoprotein (LDL) cholesterol levels are often elevated in poor glycaemic control. Epidemiological data show that total cholesterol is as powerful risk factor for coronary heart disease (CHD) in NIDDM patients as in nondiabetic subjects. High total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals, but more prospective studies are needed to substantiate this view. Compositional changes in LDL and VLDL particles may further increase the risk of CHD but epidemiological data are missing to support this notion.

The aim of this study was to compare the effect of family history of non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) as risk factors for CHD morbidity and mortality. Altogether, 394 siblings of NIDDM probands and non-diabetic probands, with and without CHD, were followed for 8 years with respect to CHD events in a prospective population-based study. The baseline study was conducted from 1983 to 1985. Age- and sex-adjusted cumulative occurrence of CHD events was higher in the siblings of the probands with CHD and with NIDDM (13.1%; P = 0.037) and in the siblings of the probands with CHD and without NIDDM (15.4%; P = 0.054), compared with the siblings of the probands without NIDDM and without CHD (4.8%). The incidence of fatal CHD events tended to be higher in a group with a family history of NIDDM and CHD, but the trend was not statistically significant. In univariate logistic regression analyses, a family history of CHD was positively associated with cumulative occurrence of CHD events (odds ratio 2.53, P = 0.009), whereas a family history of NIDDM had no significant association (odds ratio 1.39, P = 0.312). After adjustment for age, sex, family history of NIDDM and major cardiovascular risk factors, the association between family history of CHD and cumulative occurrence of CHD events remained significant (odds ratio 2.25, P = 0.048). In conclusion, the present study indicates that a family history of CHD is a stronger predictor of future CHD events than a family history of NIDDM.

Objective: It has been suggested that Chlamydia pneumoniae, a Gram-negative intracellular bacterium, is a risk factor for both myocardial infarction and chronic coronary heart disease. Previous studies have been done predominantly in non-diabetic subjects and thus the effect of diabetes on the association between C. pneumoniae antibodies and coronary heart disease has not been analysed. The aim of our study was to investigate the association between prior chlamydial infection and the risk of serious coronary heart disease events (myocardial infarction or coronary death) in a 7-year prospective study of cohorts of diabetic and non-diabetic subjects in two areas of Finland., Results: It was found that the prevalence of elevated chlamydial antibodies at baseline was higher in nondiabetic subjects who had serious coronary heart disease events during the follow-up than in subjects without coronary heart disease events (32 vs 15%, relative risk 2.56, P = 0.013) in East Finland. In non-diabetic subjects living in West Finland we did not find this association. The association between the C. pneumoniae antibodies and coronary heart disease events did not markedly change after controlling for other risk factors for coronary heart disease (OR 2.44, P = 0.055) in non-diabetic subjects living in eastern Finland. In diabetic patients we did not find any association between chlamydial antibodies and coronary heart disease events., Conclusion: We found an association between C. pneumoniae antibodies and coronary heart disease events in non-diabetics living in eastern Finland. This association remained strong even after controlling for the other risk factors for coronary heart disease. In diabetic patients with high risk for coronary heart disease, C. pneumoniae was not a risk factor for coronary heart disease.

Purpose: To review population-based studies that investigated the association and nature of association between glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus (NIDDM)., Data Sources: Study 1 included 133 newly diagnosed patients with NIDDM from eastern Finland, who were 45 to 64 years of age at baseline. These patients were followed up to 10 years for cardiovascular mortality. Study 2 included 229 newly or previously diagnosed patients with NIDDM from eastern Finland, aged 65 to 74 years at baseline. These patients were followed up to 3.5 years for coronary heart disease mortality and all coronary heart disease events (mortality or nonfatal myocardial infarction)., Study Selection: Prospective, population-based studies that included indicators of glycemic control and the evaluation of coronary heart disease and cardiovascular risk., Results: Study 1: 10-year cardiovascular mortality was significantly and linearly associated with glycemic control (fasting blood glucose and glycated hemoglobin A1 levels) independently of the mode of treatment. A high fasting blood glucose level significantly predicted cardiovascular mortality in multiple logistic regression analysis independently of other risk factors. Study 2: Glycated hemoglobin A1c was the most important single risk factor associated with coronary heart disease death or all coronary heart disease events. In multiple logistic regression analysis, glycated hemoglobin A1c was significantly associated with coronary heart disease death after adjustment for other cardiovascular risk factors., Conclusions: Two prospective, population-based studies from Finland give evidence for the linear association of glycemic control with the risk for coronary heart disease in middle-aged and elderly patients with NIDDM.

The allele e4 (apo e4) of apolipoprotein E (apo E) has been associated with an increased risk for coronary heart disease (CHD) in cross-sectional studies in middle-aged subjects. We investigated the risk of CHD and stroke with respect to the number of apo e4 alleles in a prospective study of a Finnish nondiabetic cohort including 1067 subjects 65 to 74 years old at baseline. During the 3.5-year follow-up, CHD mortality was 2.8%, total CHD incidence 6.9%, and the cumulative occurrence of CHD (prevalence at baseline and the 3.5-year incidence combined) 17.0%. The incidence of stroke was 3.4%, and the cumulative occurrence of stroke was 6.0%. The CHD mortality was 3.4% in subjects with no apo e4 allele (n = 734), 1.7% in those with one apo e4 allele (n = 296), and 0% in subjects with two apo e4 alleles (n = 37) (P = NS between the three groups). The incidence of CHD according to the number of apo e4 alleles was 6.9% (no apo e4 alleles), 7.4% (one apo e4 allele), and 2.7% (two apo e4 alleles), and the cumulative occurrence of CHD was 16.5%, 18.6%, and 13.5%, respectively (P = NS). The incidence of stroke was 3.8% in subjects with no apo e4 allele, 2.7% in those with one apo e4 allele, and 0% in those with two apo e4 alleles (P = NS). The cumulative occurrence of stroke was 6.0%, 6.4%, and 2.7%, respectively (P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Finland has marked regional differences in the occurrence of coronary heart disease (CHD). Although the causes for these differences in CHD mortality and morbidity in the Finnish population are unknown, it offers an excellent opportunity to investigate the effects of non-insulin-dependent diabetes mellitus (NIDDM) on CHD risk in two populations differing significantly with respect to the occurrence of CHD. Therefore, we carried out a 7-year prospective population-based study including a large number of patients with NIDDM (East Finland: 253 men and 257 women; West Finland: 328 men, 221 women) and corresponding non-diabetic subjects (East Finland: 313 men, 336 women; West Finland: 325 men, 399 women). In both study populations the presence of NIDDM increased significantly the risk for CHD events (CHD mortality or all CHD events including CHD mortality or non-fatal myocardial infarction). Diabetic men had 3-4 fold higher and diabetic women 8-11-fold higher risk for CHD than corresponding non-diabetic subjects. Both non-diabetic and diabetic subjects had odds ratios (East vs West) for CHD events of about 2 indicating a similar East-West difference in the CHD risk. Regional difference was quite similar in men and women. These results imply that factors related to NIDDM, independently of conventional risk factors and the occurrence of atherothrombosis in the background population, must play a major role in the pathogenesis of atherosclerotic vascular disease in NIDDM diabetes.

Background: Both hyperinsulinemia and microalbuminuria have been shown to increase coronary heart disease (CHD) risk, but the interaction among hyperinsulinemia, microalbuminuria, and the risk for CHD has not been investigated in previous studies., Methods and Results: The risk of CHD in relation to hyperinsulinemia and microalbuminuria was examined in a cohort of 1069 elderly nondiabetic subjects from Kuopio, east Finland, during 3.5 years of follow-up. The overall incidence of CHD death was 2.8%, and 6.9% of study subjects died of CHD or had a nonfatal myocardial infarction (later referred to as all CHD events). In the highest fasting-insulin quintile (fasting insulin > or = 114.0 pmol/L), there was a slightly but insignificantly higher incidence rate of both CHD mortality and all CHD events compared with lower quintiles. The incidence rates of CHD mortality and all CHD events were significantly higher in the highest urinary albumin/creatinine ratio (ACR) quintile (ACR > or = 3.22 mg/mmol) compared with lower quintiles (P < .05 and P < .01, respectively). Hyperinsulinemic microalbuminuria (simultaneous presence of fasting insulin > or = 114.0 pmol/L and ACR > or = 3.22 mg/mmol) markedly increased the risk of CHD mortality (12.5%, P < .001) and all CHD events (18.8%, P < .001) compared with normoinsulinemic subjects without microalbuminuria (2.2% and 5.8%, respectively). In univariate logistic regression analyses, hyperinsulinemic microalbuminuria was a strong predictor of both CHD death (odds ratio [OR], 5.93; P < .001) and all CHD events (OR, 3.39; P = .002). Multivariate logistic regression analyses were also performed, including sex, current smoking, waist-hip ratio, systolic blood pressure, and HDL cholesterol, with insulin, ACR, or both as independent variables. Even after adjustment for these variables, hyperinsulinemic microalbuminuria remained a strong predictor of CHD death (OR, 7.91; P < .001) and all CHD events (OR, 2.95; P = .014). The group with hyperinsulinemic microalbuminuria was characterized by the most adversely affected risk factor pattern (high triglycerides > or = 2.3 mmol/L, low HDL cholesterol < or = 0.9 mmol/L in men and < or = 1.20 mmol/L in women, and hypertension)., Conclusions: Simultaneous occurrence of hyperinsulinemia and microalbuminuria identifies a group of subjects with a highly increased risk for CHD in elderly nondiabetic subjects.

The aim of this study was to evaluate whether noninsulin-dependent diabetes (NIDDM) and its metabolic control and duration predict coronary heart disease (CHD) events during a 3.5-year follow-up in a randomly selected Finnish population sample 65-74 years of age at baseline. Of 1,298 subjects participating in the baseline study, 1,069 were nondiabetic and 229 had NIDDM. During the follow-up, 3.4% of nondiabetic and 14.8% of NIDDM subjects died from CHD or had a nonfatal myocardial infarction (MI). The impact of NIDDM on CHD mortality and morbidity was more marked in women than in men. Odds ratios (ORs) and their 95% confidence intervals for CHD death and nonfatal MI in women with NIDDM compared with women with normal glucose tolerance were 11.7 (3.8-36.4) and 4.7 (3.6-6.1). In men, the corresponding ORs were 0.43 (0.1-1.9) and 1.4 (0.6-3.2). In multiple logistic regression analyses including all study subjects, NIDDM (P < 0.01), male sex (P < 0.05), and previous MI (P < 0.01) predicted CHD death (n = 45). NIDDM (P < 0.01), male sex (P < 0.05), previous MI (P < 0.05), current smoking (P < 0.001), systolic blood pressure (P < 0.001), and low high-density lipoprotein cholesterol (P < 0.01) predicted all CHD events (CHD death or nonfatal MI) (n = 107). In NIDDM subjects, only glycated hemoglobin A1c (GHbA1c) at baseline (P < 0.01) and duration of diabetes (P < 0.05) predicted CHD death (n = 15) and all CHD events (n = 33). There was a significant increase in the risk of CHD death and all CHD events in NIDDM subjects with GHbA1c levels higher than 7.0% compared with diabetic subjects with lower GHbA1c (ORs 4.3 [1.1-16.7] and 2.2 [1.0-5.1]). In conclusion, NIDDM and its metabolic control and the duration of diabetes are important predictors of CHD in elderly subjects, particularly in women.

Background: The aim of this study was to investigate the association of lipoprotein fractions with the future risk of coronary heart disease (CHD) in patients with non-insulin-dependent diabetes (NIDDM)., Methods and Results: At baseline, lipoprotein fractions were determined in 313 diabetic patients with NIDDM (153 men and 160 women), and these patients were followed up for 7 years with respect to CHD events (CHD death or all CHD events including CHD death or nonfatal myocardial infarction). Altogether, 56 NIDDM patients (28 men and 28 women) died from CHD and 25 had a nonfatal myocardial infarction (17 men and 8 women) during the follow-up. NIDDM patients having these CHD events during the follow-up had higher levels of total and very-low-density lipoprotein (VLDL) triglycerides and VLDL cholesterol and lower levels of high-density lipoprotein (HDL) and HDL2 cholesterol than those without CHD events. The risk for CHD death was fourfold and for all CHD events, twofold higher among diabetics with low HDL cholesterol (< 0.9 mmol/L) than among diabetics with HDL cholesterol > or = 0.9 mmol/L. High triglyceride level (> 2.3 mmol/L) was associated with a twofold increase in the risk of CHD events. In multiple logistic regression analyses, HDL was inversely associated with CHD events and VLDL triglycerides with CHD events in NIDDM patients with low HDL cholesterol level (< or = 1.12 mmol/L)., Conclusions: Our 7-year follow-up study gives evidence that low HDL and HDL2 cholesterol, high VLDL cholesterol, and high total and VLDL triglycerides are powerful risk indicators for CHD events in patients with NIDDM:

The relation between plasma insulin level and the prevalence of coronary heart disease was studied in a representative nondiabetic population sample of 396 men and 673 women aged 65-74 years in Kuopio, eastern Finland, in 1986-1988. No association between plasma insulin levels and the prevalence of previous myocardial infarction was seen, except for a positive relation between 2-hour insulin level and myocardial infarction in women (4.1, 4.1, and 11.9%, p < 0.01; insulin quintiles I+II, III+IV, and V, respectively). However, the prevalence of ischemic electrocardiographic changes increased by quintiles of fasting plasma insulin (not significant) and 2-hour plasma insulin (39.8, 50.6, and 59.5% in men, p < 0.01; 35.9, 39.0, and 53.0% in women, p < 0.01). Furthermore, the prevalence of angina pectoris increased by fasting insulin (19.3, 19.0, and 33.8%, in men, p < 0.05; not significant in women) and 2-hour insulin quintiles (11.2, 28.8, and 30.4% in men, p < 0.001; 17.0, 17.8, and 28.4% in women, p < 0.05). There was a marked clustering of risk factors, including high total triglyceride levels, low high density lipoprotein cholesterol levels, and hypertension in subjects in the highest insulin quintiles. The association between insulin levels and coronary heart disease, except for myocardial infarction in women, diminished in multivariate analyses. In conclusion, hyperinsulinemia was related to an increased prevalence of coronary heart disease in elderly subjects which may be due to in part to adverse alterations in other risk factors associated with hyperinsulinemia.